Antisense oligonucleotides targeting cooperating oncogenes

United States Patent 5734039

Therapeutic combinations of two or more antisense oligonucleotides are provided. At least one first antisense oligonucleotide specific for a cytoplasmic oncogene or proto-oncogene and at least one second antisense oligonucleotide specific for a nuclear oncogene or proto-oncogene are combined for treatment of a neoplastic disease. The first antisense oligonucleotide may be specific for, e.g., a ras or raf gene, or an oncogene which codes for a protein tyrosine kinase. The nuclear gene-targeting antisense oligonucleotide preferably may be specific for a nuclear oncogene or proto-oncogene which encodes a transcriptional factor. The combined oligonucleotides have enhanced activity against neoplastic disease.

Calabretta, Bruno (Philadelphia, PA)
Skorski, Tomasz (Philadelphia, PA)

08/306691

03/31/1998

09/15/1994

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Thomas Jefferson University (Philadelphia, PA)

536/24.500

C12N15/11; A61K38/00; C07H21/04

435/91.1, 435/91.21, 435/91.41, 435/172.3, 435/320.1, 536/23.1, 536/24.5, 536/22.1, 514/44, 935/34

Morishita et al. (1994) J. Clin. Invest. 93:1458-1464.
Morishita et al. (1993) Proc. Natl. Acad. Sci. USA 90:8474-8478.
Genesis Report-Rx (1994) 3.
Hunter (1991) Cell 64:249-270.
Tidd et al. (1988) Anti-Cancer Drug Des. 3:117-127.
Amini et al. (1986) Mol. Cell. Bio. 6:2305-2316.
Heikkila et al. (1987) Nature 328:445-449.
Szczylik et al. (1991) Science 253:562-565.

Guzo, David

Schwartzman, Robert

Seidel, Gonda, LaVorgna & Monaco, PC

We claim:

1. A composition comprising at least one first antisense oligonucleotide specific for a cytoplasmic oncogene or proto-oncogene selected from the group consisting of ras genes, raf genes, EGF-1, c-fms, c-ros, c-kit, c-met, c-trk, c-src, c-abl, bcr-abl, c-fgr and c-yes and at least one second antisense oligonucleotide specific for a nuclear oncogene or proto-oncogene selected from the group consisting of myc genes, jun genes, c-ets, c-fos, c-myb, B-myb, c-rel, c-vav, c-ski, c-spi, cyclin D1, PML/RARα, AML1/MTG8, E2A/prl and ALL-1/AF-4.

2. The composition according to claim 1 wherein the first antisense oligonucleotide is specific for an oncogene or proto-oncogene which encodes a protein tyrosine kinase.

3. The composition according to claim 1 wherein the first antisense oligonucleotide is specific for bcr-abl.

4. The composition according to claim 1 wherein the first antisense oligonucleotide is specific for a cytoplasmic oncogene or proto-oncogene selected from the group consisting of ras and raf genes.

5. The composition according to claim 1 wherein the second antisense oligonucleotide is specific for an oncogene or proto-oncogene which encodes a transcriptional factor.

6. The composition according to claim 1 wherein the second antisense oligonucleotide is specific for a myc gene.

7. The composition according to claim 1 wherein the first antisense oligonucleotide is specific for a ras or raf gene, and the second antisense oligonucleotide is specific for a myc gene or a jun gene.

8. The composition according to claim 1 wherein the first antisense oligonucleotide forms a stable duplex with a portion of an mRNA transcript of a cytoplasmic oncogene or proto-oncogene, and the second antisense oligonucleotide forms a stable duplex with a portion of an mRNA transcript of a nuclear oncogene or proto-oncogene.

9. The composition according to claim 1 further comprising a pharmaceutically acceptable carrier.

10. The composition according to claim 3 wherein the second antisense oligonucleotide is specific for c-myc.

11. The composition according to claim 8 wherein the first antisense oligonucleotide forms a stable duplex with a portion of an mRNA transcript lying within about 50 nucleotides of the translation initiation codon of the cytoplasmic oncogene or proto-oncogene mRNA, and the second antisense oligonucleotide forms a stable duplex with a portion of an mRNA transcript lying within about 50 nucleotides of the translation initiation codon of the nuclear oncogene or proto-oncogene mRNA.

12. The composition according to claim 8 wherein the oligonucleotides comprise from 12-mers to 50-mers.

FIELD OF THE INVENTION

The invention relates to antisense oligonucleotides, in particular to antisense oligonucleotides to oncogenes, and the use of such oligonucleotides to inhibit proliferation of neoplastic cells.

BACKGROUND OF THE INVENTION

Proto-oncogenes are normal cellular genes the alteration of which engenders a transforming allele or "oncogene" Damage to one or more proto-oncogenes has with some consistency been found in a variety of human malignancies, causing changes in gene expression or in the gene product itself. Some of the more consistent correlations between disease occurrence and alterations in proto-oncogene expression or gene product include the following. The list is representative, not exhaustive.

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Proto-Oncogenes and Human Tumors Proto- Oncogene Neoplasm(s) Lesion

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abl Chronic myelogenous leuke- Transloca- mia; lymphoma tion erbB-1 Squamous cell and lung car- Amplifica- cinoma; astrocytoma; glio- tion blastoma; leukemia erbB-2 Adenocarcinoma of breast, Amplifica- ovary and stomach tion fos osteoblastoma Overexpres- sion gip Carcinoma of ovary and ad- Point muta- renal gland tions gsp Adenoma of pituitary gland; Point muta- carcinoma of thyroid tions kit leukemia and lymphoma myc Burkitt's lymphoma; leuke- Transloca- mia; carcinoma of lung, tion breast and cervix; myeloma; Amplifica- neuropithelioma tion myb leukemia, lymphoma, mela- noma, colorectal carcinoma; neuroectodermal tumors L-myc Carcinoma of lung Amplifica- tion N-myc Neuroectodermal tumors Amplifica- (neuroblastoma and neuroe- tion pithelioma); small cell carcinoma of lung neu breast and ovarian carcino- Amplifica- ma tion H-ras Carcinoma of colon, lung, point muta- and/or prostate, bladder, breast, tions K-ras thyroid and pancreas; mela- noma; acute myelogenous and lymphoblastic leukemia; carcinoma of thyroid N-ras Carcinoma of genitourinary Point muta- tract and thyroid; melano- tions ma; leukemia ret Carcinoma of thyroid Rearrange- ment ros Astrocytoma ? K-sam Carcinoma of stomach Amplifica- tion sis Astrocytoma ? src Carcinoma of colon ? trk Carcinoma of thyroid Rearrange- ment

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As may be appreciated from the above table, a large number and variety of human tumors contain consistent point mutations in ras proto-oncogenes. Chromosomal translocations also contribute to tumorigenesis by activating proto-oncogenes to oncogenes, e.g., the translocation of c-abl to the BCR locus to form the hybrid oncogene bcr-abl which has been correlated with the occurrence of Philadelphia chromosome-positive leukemias. Other tumors carry abnormally amplified domains of DNA that can include proto-oncogenes and magnify their expression (Alitalo & Schwab, Adv. Cancer Res. 47, 235-282, 1986). The potential of proto-oncogenes to participate in tumorigenesis arises from the fact that their protein products are relays in the biochemical circuitry that governs the phenotype of vertebrate cells (Bishop, Cell 64, 235-248, 1991).

The three biochemical mechanisms by which proto-oncogenes act were recently reviewed by Bishop, id. The first mechanism is by phosphorylation of proteins at serine, threonine or tyrosine residues. The immediate role of the proto-oncogene product may be induction of the phosphorylation (as with some growth factors) or catalysis itself (as with the receptors for some growth factors). The second mechanism of proto-oncogene action is transmission of signals by GTPases (Bourne et al., Nature, 348, 125-131, 1990. The ras family of oncogenes encode a variety of GTPase. Moreover, at least some heterotrimeric G proteins can also transform cells when suitably mutant in their α subunits. The corresponding proto-oncogenes are known as gsp (stimulatory G proteins) and gip (inhibitory G proteins). The third mechanism of proto-oncogene action consists of control of transcription from DNA. A variety of transcription factors, discussed below, are encoded by proto-oncogenes.

Oncogenes/proto-oncogenes are broadly subdivided into two major groups: nuclear and cytoplasmic. This distinction is of course based upon on the cellular location of the encoded proteins and/or their place of action, but has also acquired a broader meaning in relationship to the model of tumorigenic conversion of primary embryo fibroblasts that is based on the cooperation between the cytoplasmic oncogene c-ras and the nuclear oncogene c-myc (Land et al., Nature 304, 602-606, 1983).

The proto-oncogenes which encode proteins localized in the nucleus participate in the regulation of the proliferation of mammalian cells. They are believed to be directly involved in the regulation of gene expression that leads to cell proliferation, division, and differentiation. Many of these proteins are able to bind DNA. Studies have shown that transient expression of nuclear protein-encoding proto-oncogenes is required for cells to traverse specific points in the cell cycle.

Nuclear proto-oncogenes which comprise transcription factors include, for example, erbA, evi-1, gli-1, maf, lyl-1, ets-1, ets-2, fos, jun, myb, myc, rel, vav, ski, and spi-1. The indicated genes may in some cases comprise a group of variants identified under a common name. For example, the jun family includes at least three distinct genes--c-jun, c-jun-B and c-jun-D. Antisense oligonucleotides hybridizable to the relevant mRNA may be prepared, based upon reported cDNA sequences. The following is a partial listing of references reporting DNAs for the indicated proto-oncogenes and/or reports of inhibition of cell proliferation with antisense oligonucleotides specific for the targeted genes:

c-myc--Gazin et al., EMBO J. 3:383-387, 1984 (cDNA); Wickstrom et al., Proc. Natl. Acad. Sci. USA85, 1028-1032 (1988); Loke et al., Clin. Res. 36(3), 443A (1988); Holt et al., Cell. Biol. 8, 963-973 (1988); Yokoyama et al., Proc. Natl. Acad. Sci. USA 84, 7363-7367 (1987); Harel-Bellan et al., J. Immunol. 140, 2431-2435 (1988) (inhibition of growth of leukemic cells by antisense oligonucleotides);

L-myc--Kaye et al., Mol. Cel.Biol. 8:186-195, 1988 (cDNA);

N-myc--Ibson & Rabbitts, Oncogene2:399-402, 1988 (cDNA);

c-jun--Hattori et al., Proc. Natl. Acad. Sci. USA 85:9148-9152, 1988 (cDNA);

c-fos--van Straaten et al., Proc. Natl. Acad. Sci. USA 80:3183-3187, 1983 (cDNA); Nercola et al., Biochem. Biophys. Res. Comm. 147, 288-294 (1987); Groger et al., Proc. Am. Assoc. Caner Res. 29, 439 (1988) (inhibition of growth of transformed cells by antisense oligonucleotide);

c-myb--Majello et al., Proc. Natl. Acad. Sci. USA 83:9636-9640, 1986 (cDNA);

B-myb--Nomura et al., Nucl. Acid Res. 16:11075-11090, 1988 (cDNA);

cyclin D1 (also known as bcl-1)--Xiong et al., Cell 65. 601-699, 1991 (cDNA).

The following is a partial listing of nuclear oncogenes, formed by translocation events. Each citation reports the relevant cDNA sequence. The oncogenes are established or purported transcriptional factors.

PML/RARα--Kakizura et al., Cell, 66:663-674, 1991;

DEK/CAN--von Linden et al., Mol. Cell. Biol., 12: 1687-1697, 1992;

AML1/MTG8--Miyoshi et al., EMBO J. 12:2715-2721, 1993;

E2A/prl--Nouse et al., Cell, 60: 535-545, 1990; Kamps et al., Cell, 60: 547-555 1990;

ALL-1/AF-4--Gu et al., Cell 71: 701-708, 1992.

Nucleotide sequences of various other oncogenes/-proto-oncogenes are disclosed in International Patent Application WO 94/00473, the entire disclosure of which is incorporated herein by reference.

Certain of the nuclear oncogenes/proto-oncogenes code for proteins with DNA-binding activity. The nuclear proto-oncogenes comprising the jun family (c-jun, jun-B and jun-D), c-myb, the proto-oncogenes comprising the c-ets family (c-ets-1 and c-ets-2), and c-myc, recognize specific nucleotide core sequences.

The proto-oncogene c-jun, which encodes the transcription activator protein AP-1, has been shown to bind to a specific heptameric consensus sequence TGACTCA (Bohmann et al., Science 238, 1386-1392, 1987; Angel et al., Nature 332, 166-1711, 1988). Jun-B has extensive amino acid sequence similarity to c-jun in the region that encodes the DNA-binding domain and, as expected, binds to the same DNA consensus sequence (Nakageppu et al., Cell 5, 907-915, 1988); jun-D, the third number of this family, behaves similarly (Nakageppu et al., 1988). The proteins encoded by c-ets-1 and c-ets-2 genes bind to a 14-base pair sequence from the oncogene-responsive domain of the polyoma enhancer, in which the ACTTCCT appears to be the essential portion of the domain (Wasylyk et al., Nature 346,191-193, 1990). The DNA-binding activity also appears to be localized at the carboxy-terminal region of the c-ets-encoded protein (Wasylyk et al., 1990).

c-Myb encodes a protein that binds to a specific core sequence (pyAACG/TG) (Biedenkapp et al., Nature bv3351, 835-837, 1988). The DNA-binding activity of c-myb, unlike that of the c-jun and c-ets gene families, is localized in the amino-terminal portion of the protein (Klempnauer and Sippel, 1987). The c-fos product has been shown to bind nonspecifically to DNA (Renz et al., Nucleic Acid Res. 15, 277-292, 1987); however, when complexed to c-jun encoded proteins, the c-fos product has a marked stimulatory effect on their binding to AP-1 sites (Chiu et al., Cell 59, 979-986, 1988; Halazonetis et al., Cell 55, 917-924, 1988). The human c-myc protein is a DNA-binding protein exhibiting a high nonspecific activity for double-stranded DNA (Persson et al., Science 225, 718-721, 1984; Watt et al., Mol. Cell. Biol. 5, 448-456, 1985). Recently, it has been shown that a purified carboxyl terminal fragment of human c-myc binds in vitro in a sequence-specific manner to the sequence CACGTG (Blackwell et al., Science 250, 1149-1151, 1990).

c-Myb up-regulates the expression of reporter genes linked to myb-binding sites (Weston and Bishop, Cell 58, 85-93, 1989; Sakura et al., Proc. Natl. Acad. Sci. U.S.A. 86, 5758-5762, 1989) and the cellular gene MIM-1, whose expression is promyelocytic-specific, appears to be directly regulated by c-myb and contains myb-binding sites in the 5' flanking region (Ness et al., Cell 59, 1115-1125, 1989). The MYB protein binds to DNA by virtue of an N-terminal region that contains a triple repeat.

The CD34 antigen defines a subset of hematopoietic progenitor cells with self-renewal capacity and the ability to reconstitute hematopoiesis in irradiated primates and marrow-ablated humans. The c-myb gene plays a fundamental role in hematopoiesis, most likely through its transcriptional regulator function. The MYB protein transactivates the CD34 promotor via specific interaction with multiple MYB binding sites in the 5' flanking region of the CD34 antigen gene and induces expression of the endogenous CD34 mRNA in rodent fibroblasts, directly demonstrating that c-myb regulates the expression of the CD34 antigen (Melotti o et al., J. Exp. Med. 179, 1023-1028, 1994).

It has been suggested that c-ets-1 and c-ets-2 transactivate the expression of reporter genes linked to c-ets binding sites; the c-ets binding domain is contiguous with the AP-1 binding site in the polyoma (Py) enhancer; this association generates a responsive element that is highly stimulated by the concomitant expression of c-jun and c-ets (Wasylyk et al., 1990). The c-rel gene is also a regulator of transcription.

ErbA is another nuclear oncogene whose protein product binds nucleic acid. It codes for a thyroid hormone receptor, a member of the class of steroid hormone receptors. Upon binding its ligand, asteroid receptor activates expression of particular target genes by binding to its specific response element in a promotor or enhancer. These receptors, such as erbA, are therefore transcription factors that respond to binding particular ligands.

Cytoplasmic oncogenes/proto-oncogenes include members of the ras and raf families of oncogenes, as well as various protein kinase types, most notably the protein tyrosine kinases.

The ras gene family members are found expressed in human cancers more often than any other oncogene. Three ras genes have been characterized, designated c-H-ras, c-K-ras and c-N-ras. The three genes all encode proteins of 21,000 daltons molecular weight generally known as p21 ^ras . These proteins are very homologous in amino acid sequence differing primarily at their C terminii. The cDNA sequences for each of the H-, K-and N-ras genes have been reported (Capon et al., Nature 302, 33-37, 1983; Kahn et al., Anticancer Res. 7, 639-652, 1987; Hall & Brown, Nucl. Acid Res. 13, 5255-5268, 1985).

The p21 ^ras proteins belong to a family of signal-transducing monomeric proteins with GTP-binding activity and appear to play a central role in signal transduction pathways (Bourne et al., Nature 348:125 (1990-)). The IL-2, IL-3, CSF-1, GM-CSF, EGF, SCF and PDGF receptors (Satoh et al., Proc. Natl. Acad. Sci. USA88:3314 (1991); Duronio et al., Proc. Natl. Acad. Sci. USA 89:1587 (1992); Satoh et al., Proc. Natl. Acad. Sci. USA 87:5993 (1990); Satoh et al., Proc. Natl. Acad. Sci. USA 87:7926 (1990; Gibbs et al., J. Biol. Chem. 265:20437 (1990)), and several oncogene products with constitutively enhanced tyrosine kinase activity (fms, src, abl, bcr-abl) (Gibbs et al., J. Biol. Chem. 265:20437 (1990); Smith et al., Nature 320:540 (1986); Mandanas et al., Blood 80 (Suppl.1):14a (1992)), activate p21 ^ras proteins.

The p21 ^ras proteins bind guanine nucleotides with high affinity and hydrolyze GTP with low catalytic efficiency. p21 ^ras is activated by the replacement of GDP by GTP, a process that is catalyzed by a guanine nucleotide-releasing factor. In the GTP form, p21 ^ras proteins serve as signal transducers (Smith et al., Nature 320:540 (1986); Trahey and McCormick Science 238:542 (1987)) but are inactive in the GDP-bound form.

In mammalian cells two proteins, p120 rasGTPase activating protein ("rasGAP" or "p120-GAP") and NF-1, inactivate p21 ^ras (Bollag and McCormick, Annu. Rev. Cell. Biol. 7:601 (1992)) by inducing a 100-fold increase of the intrinsically low GTPase activity of p21 ^ras , which converts the active GTP-bound form to the inactive GDP-bound form by stimulation GTP-GDP exchange (Trahey and McCormick, Science 238:542 (1987)). The active p21 ^ras -GTP-bound form of p21 ^ras is inactivated by an intrinsic GTPase activity that is catalyzed by the carboxylterminus domain of p120-GAP (Marshall et al., EMBO (Eur. Mol. Biol. Organ) J. 8:1105 (1989)).

It has been shown that p21 ^ras plays an important role in the formation of normal and leukemic hematopoietic colonies (Skorski et al., J. Exp. Med. 175:743, 1992), and that p120-GAP is an inhibitor of p21 ^ras . A decrease in the GTPase activity observed in the activated ras oncogene product is believed to be responsible for its transforming activity (Seeburg et al., Nature 312:71, 1984). Thus, the binding of GTP with the diminished capacity to hydrolyze it would maintain the protein in a constitutively active state, thus sending a continuous signal to the cell along the mitogenic pathway.

The raf proto-oncogene codes a protein-serine/threonine kinase. The activity of this enzyme is induced by direct or indirect action of diverse cell surface receptors, cytoplasmic protein tyrosine kinases, and ras (Morrison et al., Proc. Natl. Acad. Sci. USA 85, 8855-8859, 1988; Morrison et al., Cell 58, 649-657, 1988). The cDNA sequence for the c-raf gene has been reported (Bonner et al., Nucl. Acid Res. 14, 1009-1015, 1986).

The protein tyrosine kinases encompass a large diverse group of oncogenes and proto-oncogenes which encode proteins which catalyze the transfer of a phosphate residue from a nucleoside triphosphate to the side chain of a tyrosine residue in a protein. The transforming potential of protein tyrosine kinases is activated by N-terminal or C-terminal rearrangements. These alterations may remove down-regulating domains of the protein and result in the constitutive activation of what is normally a conditionally regulated enzyme activity. Thus, when suitably mutated (or, in some instances, anomalously expressed), protein tyrosine kinases themselves become transforming proteins, acting through unwanted phosphorylation of their diverse substrates. Further, protein tyrosine kinases can be vehicles for transformation by disturbances elsewhere in signalling pathways., e.g., constitutive production of growth factors that act through protein tyrosine kinase receptors (Aaronson & Pierce, Cancer Cells2, 212-214, 1990) and the effects of phosphatases, which play crucial roles in governing the activity of protein tyrosine kinases (Hunter, Cell 58, 1013-1016, 1989).

One type of tyrosine protein kinase comprises the transmembrane protein kinases which span the plasma membrane. They contain large extracellular and cytoplasmic domains. One such category comprises the EGF family of growth factor receptors. The receptor has intrinsic tyrosine kinase activity that is activated by the binding of its ligand. EGF-1 is expressed in breast cancers and glioblastomas. EGF ₂ is found expressed in neuroblastomas. The cDNA sequence corresponding to the former is reported by Helin et al., Cell 70, 337-350 (1992).

Further examples of the tyrosine kinase growth factor receptor family include erbB, fms, ros, kit, met, trk and neu oncogenes. Expression of met has been found in gastric carcinomas. The cDNA sequence of c-kit was reported by Vandenbark et al., Oncogene7, 1259-1266 (1992).

Another type of tyrosine kinases includes a large number of nonintegral membrane-associated protein tyrosine kinases. The protein product of v-src, the prototype of this family, is associated with the plasma membrane but does not traverse the membrane. Oncogenic p60 ^v -src encoded in Rous sarcoma virus and its cellular homolog p60 ^c -src, are membrane-localized phosphoproteins that possess protein tyrosine kinase activity. The cDNA sequence of the normal cellular homologue, the proto-oncogene c-src, has been reported (Braeuninger et al., Proc. Natl. Acad. Sci. USA 88, 10411-10415, 1991). Normal p60 ^c -src is tightly regulated in its kinase activity relative to p60 ^v -src and generally is not oncogenic. Mutations in p60 ^c -src that elevate its kinase activity also activate its oncogenic potential. It has been suggested that p60 ^v -src and p60 ^c -src associate with complexes containing p120-GAP and provide a biochemical link between these kinases and p120-GAP/ras traduction pathways (Brott et al., Proc. Natl. Acad. Sci. USA 88, 755-759 , 1991).

Other members of the tyrosine kinase family include fes, abl, fgr and yes. All of these proto-oncogene products are homologous in their tyrosine kinase domains. The tyrosine kinase domains as in the growth factor receptor tyrosine kinase family, is responsible for catalyzing the transfer of phosphate groups from ATP to tyrosine residues during auto-phosphorylation or transphosphorylation of target molecules.

The aberrant expression of a nonintegral membrane associated tyrosine kinase is best illustrated by the abl proto-oncogene, the cDNA sequence of which is reported by Shtivelman et al., Cell 47, 277-284 (1986). Aberrant expression of abl results from the c-abl gene's translocation from the long arm of chromosome 9 to the breakpoint cluster region (bcr) on chromosome 22, resulting in the formation of bcr-abl hybrid genes. The break occurs near the end of the long arm of chromosome 9 (band 9q34) and in the upper half of chromosome 22 (band 22q11). The chimeric message is in turn translated into a larger chimeric abl protein (210 kDa) that has increased tyrosine kinase activity (Konopka et al., Cell 37, 1035 (1984); Kloetzer et al., Virology 140, 230 (1985); Konopka et al., Proc. Natl. Acad. Sci. U.S.A. 82, 1810 (1985)). The 210 kDa protein is considerably larger than the normal human abl protein of 145 kDa, and has a very high tyrosine kinase activity. The cDNA sequences of the various bcr-abl oncogenes have been reported: Shtivelman et al., Cell 47, 277 (1986); Mes-Masson et al., Proc. Natl. Acad. Sci. USA 83, 9768-9772 (1986); Fainstein et al., Nature 330, 386-388 (1987).

Molecular strategies are being developed to downregulate unwanted gene expression, including oncogene expression. One such strategy involves inhibiting gene expression with oligonucleotides complementary in sequence to ther messenger RNA of a deleterious target gene. The so-called "antisense" oligonucleotides have been proposed as anti-cancer agents, by targeting various oncogenes or proto-oncogenes. See, for example, U.S. Pat. No. 5,098,890 (c-myb antisense for treating hematologic neoplasms, including use in bone marrow purging); international Patent Application WO 91/93260 (c-abl antisense for treating myeloproliferative disorders); International Patent Application W092/19252 and Ratajczak et al., Proc. Natl. Acad. Sci. USA 89, 1710-1714 (1992) (c-kit for inhibiting malignant hematopoietic cell proliferation); International Patent Application W092/20348 and Melani et al., Cancer Res. 51; 2897-2901 (1991) (c-myb antisense for inhibiting proliferation of colon cancer cells); international Patent Application WO93/09789 (c-myb antisense for inhibiting malignant melanoma cell proliferation); International Patent Application WO92/22303 and Szcylick et al., Science 253, 562-565 (1991) (bcr-abl antisense for inhibiting leukemia cell proliferation); and U.S. Pat. No. 5,087,617 which describes bone marrow purging and in vivo therapy using antisense oligonucleotides to a variety of oncogenes of proto-oncogenes. The entire disclosure of each of the aforementioned references is incorporated by reference herein.

Growing evidence suggests that cancer arises through a multistep process which involves activation of proto-oncogenes and loss of function of tumor suppressor genes (Fearon et al., Cell 61, 759 (1991). Oncogene cooperation was originally demonstrated in vitro (Murray et al., Cell 33, 749 (1983); Thompson et al., Cell 56, 917 (1989); Stasser et al., Nature 348 (1990)) and subsequently validated in vivo using transgenic mouse models (Adams et al., Science 254, 1161 (1991)). Chronic myelogenous leukemia (CML) illustrates well the concept of a multistep process in human malignancies, because the clinical course consists of two well-defined stages, i.e., a relatively indolent and long lasting chronic phase, and a terminal, more aggressive blast crisis (Kantarjan et al., Blood 82, 691 (1993)). At the genetic level, the predominant abnormality of the chronic phase is the Philadelphia chromosome (Ph ¹ ) translocation resulting in the formation of the bcr-abl oncogene.

Some studies have indicated that specific combinations of oncogenes are able to cooperate to induce a transformed phenotype, and that oncogene products which act in the nucleus cooperate best with those that act in the cytoplasm. These studies have been recently reviewed by Hunter, Cell 64, 249-270 (1991).

Despite evidence of cooperation of nuclear and cytoplasmic oncogenes in transformation, there is no suggestion that simultaneous inhibition of both oncogene types can result in enhanced antitumor effect. Moreover, while antisense oligonucleotides have been indicated as being useful for the treatment of cancer, it has not been heretofore suggested to adopt multiple antisense oligonucleotides specific for diverse oncogenes to provide enhanced antineoplastic effect.

SUMMARY OF THE INVENTION

According to the present invention, a composition is provided comprising at least one first antisense oligonucleotide specific for a cytoplasmic oncogene or proto-oncogene and at least one second antisense oligonucleotide specific for a nuclear oncogene or proto-oncogene. According to one preferred embodiment of the invention, the first antisense oligonucleotide is specific for a ras or raf gene. According to another preferred embodiment, the first antisense oligonucleotide is specific for a gene which codes for a protein tyrosine kinase.

The second antisense oligonucleotide is, according to one aspect of the invention, specific for a nuclear oncogene or proto-oncogene which encodes a transcriptional factor.

According to one embodiment, each of the first and second oligonucleotides has a nucleotide sequence capable of forming a stable duplex with a portion of an mRNA transcript of a cytoplasmic oncogene/proto-oncogene, or with an mRNA transcript of a nuclear/oncogene or proto-oncogene, respectively.

Each oligonucleotide is generally at least an 8-mer oligonucleotide, that is, the oligonucleotide is an oligomer containing at least 8 nucleotide residues, more preferably at least about 12 nucleotides. The preferred maximum size of the oligonucleotide is about 60 nucleotides, more preferably about 50 nucleotides, most preferably about 40 nucleotides. The oligomer is preferably an oligodeoxynucleotide. While oligonucleotides smaller than 12-mers may be utilized, they are statistically more likely to hybridize with non-targeted sequences, and for this reason may be less specific. In addition, a single mismatch may destabilize the hybrid. While oligonucleotides larger than 40-mers may be utilized, uptake may become somewhat more difficult without specialized vehicles or oligonucleotide carriers. Moreover, partial matching of long sequences may lead to non-specific hybridization, and non-specific effects. Most preferably, the oligonucleotide is a 15- to 40-mer oligodeoxynucleotide, more advantageously an 18- to 30-mer.

While in principle oligonucleotides having a sequence complementary to any region of the target mRNA find utility in the present invention, preferred are oligonucleotides capable of forming a stable duplex with a portion of the transcript lying within about 50 nucleotides (preferably within about 40 nucleotides) upstream (the 5' direction), or about 50 (preferably 40) nucleotides downstream (the 3' direction) from the translation initiation codon of the target mRNA. Also preferred are oligonucleotides which are capable of forming a stable duplex with a portion of the target mRNA transcript including the translation initiation codon.

The invention is also a method for inhibiting the proliferation of neoplastic cells, comprising contacting such cells with a proliferation-inhibiting effective amount of at least one first antisense oligonucleotide specific for a cytoplasmic oncogene/proto-oncogene and at least one second antisense oligonucleotide specific for a nuclear oncogene/proto-oncogene.

The invention also provides a method for treating neoplastic disease comprising administering to a patient in need of such treatment an effective amount of at least one first antisense oligonucleotide specific for a cytoplasmic oncogene/proto-oncogene and at least one second antisense oligonucleotide specific for a nuclear oncogene/proto-oncogene.

In yet another embodiment, the invention is a method for purging bone marrow of neoplastic cells such as leukemic cells, or solid tumor cells which have metastasized to the bone marrow. Bone marrow cells aspirated from an individual afflicted with a neoplastic disease are treated with an effective amount of at least one first antisense oligonucleotide specific for a cytoplasmic oncogene/proto-oncogene and at least one second antisense oligonucleotide specific for a nuclear oncogene/proto-oncogene. The thus-treated cells are then returned to the body of the afflicted individual.

According to another embodiment, the invention is an artificially-constructed gene comprising a first promotor segment and a segment containing DNA of a cytoplasmic oncogene or proto-oncogene DNA, and a second promotor segment and a segment containing DNA of a nuclear oncogene or proto-oncogene. The oncogene/-proto-oncogene DNA-containing segments are in inverted orientation such that transcription of the artificially-constructed gene produces RNA complementary to an mRNA transcript of the cytoplasmic oncogene or proto-oncogene and RNA complementary to an mRNA transcript of the nuclear oncogene or proto-oncogene. The gene may be introduced into target cells to inhibit the proliferation of those cells. The artificially-constructed gene may be introduced into the target cells by, for example, transfection, transduction with a viral vector, or microinjection.

Definitions

By "proto-oncogene" is meant a normal, cellular human gene, the alteration of which gives rise to a transforming allele or "oncogene".

By "oncogene" is meant a human gene in a host cell which is responsible, in whole or in part, for the neoplastic transformation of the host cell.

By "cytoplasmic oncogene" or "cytoplasmic proto-oncogene" is meant an oncogene/proto-oncogene the encoded protein of which is localized primarily in the cell cytoplasm.

By "nuclear oncogene" or "nuclear proto-oncogene" is meant an oncogene or proto-oncogene the encoded protein of which is localized primarily in the cell nucleus.

By "protein tyrosine kinase" is meant an enzyme which catalyzes the transfer of a phosphate residue form a nucleoside triphosphate to the side chain of a tyrosine amino acid residue in a protein.

By "transcriptional factor" is meant the product of a nuclear oncogene or proto-oncogene which binds a target DNA segment to activate transcription of another gene.

An "antisense oligonucleotide specific for" a targeted oncogene or proto-oncogene is meant an oligonucleotide having a sequence (i) capable of forming a stable triplex with a portion of the targeted oncogene, or (ii) capable of forming a stable duplex with a portion of an mRNA transcript of the targeted oncogene.

The term "oligonucleotide" as used herein includes linear oligomers of natural or modified monomers or linkages, including deoxyribonucleosides, ribonucleosides, α-anomeric forms thereof, polyamide nucleic acids, and the like, capable of specifically binding to a target polynucleotide by way of a regular pattern of monomer-to-monomer interactions, such as Watson-Crick type of base pairing, Hoogsteen or reverse Hoogsteen types of base pairing, or the like. Usually, monomers are linked by phosphodiester bonds or analogs thereof to form oligonucleotides ranging in size from a few monomeric units, e.g., 3-4, to several hundreds of monomeric units. Analogs of phosphodiester linkages include: phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phosphoranilidate, phosphoramidate, and the like, as more fully described below. As used herein, "nucleoside" includes the natural nucleosides, including 2'-deoxy and 2'-hydroxyl forms, e.g., as described in Kornberg and Baker, DNA Replication, 2nd Ed. (Freeman, San Francisco, 1992). "Analogs" in reference to nucleosides includes synthetic nucleosides having modified base moieties and/or modified sugar moieties, e.g., described generally by Scheit, Nucleotide Analogs (John Wiley, New York, 1980). Such analogs include synthetic nucleosides designed to enhance binding properties, e.g., duplex or triplex stability, specificity, or the like.

The term "phosphorothioate oligonucleotide" means an oligonucleotide wherein one or more of the internucleotide linkages is a phosphorothioate group, ##STR1## as opposed to the phosphodiester group ##STR2## which is characteristic of unmodified oligonucleotides.

By "alkylphosphonate oligonucleoside" is meant an oligonucleotide wherein one or more of the internucleotide linkages is an alkylphosphonate group, ##STR3## wherein R is an alkyl group, preferably methyl or ethyl.

The term "modified oligonucleotide" is meant an oligonucleotide containing one or more modified monomers and/or linkages to enhance the stability or uptake of the oligonucleotide.

"Stability" in reference to duplex or triplex formation roughly means how tightly an antisense oligonucleotide binds to its intended target sequence; more precisely, it means the free energy of formation of the duplex or triplex under physiological conditions. Melting temperature under a standard set of conditions, e.g., as described below, is a convenient measure of duplex and/or triplex stability. Preferably, antisense oligonucleotides of the invention are selected that have melting temperatures of at least 50° C. under the standard conditions set forth below; thus, under physiological conditions and the preferred concentrations, duplex or triplex formation will be substantially favored over the state in which the antisense oligonucleotide and its target are dissociated. It is understood that a stable duplex or triplex may in some embodiments include mismatches between base pairs and/or among base triplets in the case of triplexes. Preferably, antisense oligonucleotides of the invention form perfectly matched duplexes and/or triplexes with their target polynucleotides.

The term "downstream" when used in reference to a direction along a nucleotide sequence means the direction. Similarly, the term "upstream" means the 3'➝5' direction.

The term "targeted oncogene (or proto-oncogene) mRNA transcript" means the presently known mRNA transcript of the targeted oncogene (or proto-oncogene) and all variations thereof, or any further transcripts which may be elucidated.

The term " S!ODN" means phosphorothioate oligodeoxynucleotide.

DESCRIPTION OF THE FIGURES

FIGS. 1A, 1B and 1C contain the results of cell proliferation assays demonstrating the effects of various oligonucleotides on the proliferation of chronic myelogenous leukemia (BV173) cells at final oligonucleotide concentrations of 10 (FIG. 1A), 5 (FIG. 1B) and 2.5 (FIG. 1C) μg/ml: (.largecircle.) control; (Δ) b2/a2 plus c-myc sense; (.quadrature.) b2/a2 antisense; (.box-solid.) c-myc antisense, (.circle-solid.) b2/a2 and c-myc antisense.

FIG. 2 is a Western blot of total cellular protein from BV173 cells after 72 hours incubation with 10 μg/ml of the above oligonucleotides, treated with anti-ABL, anti-c-MYC or anti-heat shock protein (HSP) 72/73 antibody.

FIGS. 3A-3D comprise the results of flow cytometry DNA content analysis of BV173 cells incubated for 24, 48, and 72 hours in the presence of the following antisense S!ODNs: 3A, b2/a2 10 μg/ml; 3B, c-myc 10 μg/ml, 3C, b2/a2 2.5 μg/ml; 3D, b2/a2+c-myc 2.5 μg/ml.

FIG. 4 contains a series of blots of the RT-PCR amplification of bcr-abl and β-actin RNA from total RNA extracted from various organs of BV173-transplanted SCID mice 56 days post transplantation. Seven days post transplantation the, mice were systemically injected for 12 consecutive days with 1 mg/day/mouse of b2/a2 sense+c-myc sense (6 days each, every other day), b2/a2 antisense, c-myc antisense or b2/a2+c-myc antisense (6 days each, every other day). Control mice were injected with diluent only. (PBL=peripheral blood lymphocyte; SPL=spleen; BMC=bone marrow cell; LIV=liver; LNG=lung; and BRN=brain).

FIG. 5 presents the results of quantitative RT-PCR of bcr-abl transcripts in RNA isolated from bone marrow cells of b2/a2 antisense and b2/a2+c-myc antisense S!ODN-treated mice, in the presence of increasing amounts of RNA from K562 cells (b3/a2) as a source of competitive bcr-abl RNA (lane 1, no K562 RNA; lane 2, 0.1 ng; lane 3, 1 ng; lane 4, 10 ng; lane 5, 100 ng).

FIG. 6 is a plot of the survival of BV173-transplanted SCID mice treated with sense, single antisense and dual antisense S!ODNs: b2/a2 S+c-myc S (.box-solid.); b2/a2 AS (.tangle-solidup.), c-myc AS (.quadrature.); or b2/a2 AS c-myc AS (.circle-solid.). Control mice (.largecircle.) received diluent only.

FIG. 7A presents the results of a hybridization assay detecting bcr-abl (b2/a2) and c-myc antisense S!ODNs in various tissues of antisense-treated SCID mice 24 hours after conclusion of a 1 mg/day/12 consecutive day treatment with b2/a2 and c-myc antisense S!ODN.

FIG. 7B presents the results of a hybridization assay detecting bcr-abl (b2/a2) and c-myc antisense S!ODNs in CD10+BV173 cells isolated from bone marrow and spleen suspensions of mice treated in accordance with FIG. 7A. Standard 26-mer antisense S!ODNs (50 ng and 5 ng) were run as controls.

FIG. 8 contains the results of cell proliferation assays demonstrating the effectiveness of the combination of c-raf and c-myc antisense oligonucleotides on BV173 cells. Cells were treated with the indicated concentrations of oligonucleotides at the beginning of culture and again (at 50% of the initial dose) 24 and 48 hours later. Control wells received no oligomer. Sense oligonucleotide-treated cells received equal mixtures of c-raf and c-myc sense oligonucleotides. (.largecircle.) control; (.quadrature.) c-raf plus c-myc sense; (.circle-solid.) c-raf antisense; (.box-solid.) c-myc antisense; (Δ) c-raf and c-myc antisense.

FIG. 9 is similar to FIG. 8 except that ras oligonucleotides were substituted for c-raf oligonucleotides. The ras oligonucleotide-treated cells received an equal mixture of a combination of N-, K-, and H-ras oligonucleotides. The oligonucleotide dosages appear in the figure. (.largecircle.) control; (.quadrature.) ras plus c-myc sense; (.circle-solid.) c-myc antisense; (.box-solid.) ras antisense, (.tangle-solidup.) ras and c-myc antisense.

FIG. 10 is similar to FIG. 9, except that c-raf oligonucleotides were substituted for c-myc oligonucleotides. (.largecircle.) control; (.quadrature.) c-raf plus ras sense; (.circle-solid.) c-raf antisense; (.box-solid.) ras antisense; (.tangle-solidup.) c-raf and ras antisense.

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention, at least one antisense oligonucleotide specific for at least one cytoplasmic oncogene or proto-oncogene, is administered to a patient with at least one antisense oligonucleotide specific for a nuclear oncogene or proto-oncogene, preferably an antisense oligonucleotide specific for a transcriptional factor. The two antisense oligonucleotides may be administered by any of the routes described hereinafter. While it is preferred that the two agents be administered simultaneously, such as in the form of a single pharmaceutical composition, the two agents may be administered separately, in sequence. While it is presently preferred that both oligonucleotides are administered through the same route, they may be administered through different routes.

The antisense oligonuclerotide pair may comprise, for example, antisense oligonucleotides specific to any of the nuclear and cytoplasmic oncogenes/proto-oncogenes disclosed herein. Thus, for example, the targeted cytoplasmic gene may comprise c-erbB, c-fms, c-ras, c-kit, c-met, c-trk, c-neu, c-src, c-fes, c-abl, bcr-abl, c-fgr, or c-yes. Combinations of antisense oligonucleotides specific for the same or different cytoplasmic genes may be utilized. The targeted nuclear gene may comprise, for example, c-erbA, c-evi-1, c-gli-1, c-maf, c-lyl-1, c-ets, c-fos, c-jun, c-myb, c-myc, b-myb, N-myc, L-myc, c-rel, c-vav, c-ski, c-spi or cyclin D1. Combinations of antisense oligonucleotides specific for the same or different nuclear genes may be utilized. It should be appreciated that in the aforesaid listings, the indicated gene may comprise a group of variants identified under a common name, e.g., "c-jun" includes the specific genes c-jun, c-jun-B and c-jun-D.

According to one preferred embodiment of the invention, the therapeutic combination comprises one or more antisense oligonucleotides specific for a ras gene in combination with one or more antisense oligonucleotides specific for a myc gene. By "ras" is meant any of the family of ras genes, such as N-ras, c-ras or H-ras. Similarly, by "myc" is meant any of the family of myc genes, such as c-myc, L-myc and N-myc, and by "jun" is meant any of the family of jun genes such as c-jun, c-junB and c-junD. The protein tyrosine kinases encoded by src, kit, bcr-abl, fms, and the receptor type kinases (insulin, IGF-1, EGF, etc.), all converge on RAS, which in turn binds RAF, which in turn activates MAP-kinase, which in turn phosphorylates nuclear effectors such as myc. The RAS protein also activates jun, which is in turn a regulator of all growth. A combination of antisense oligonucleotides specific for ras and myc genes is thus believed particularly useful against neoplastic disorders, e.g., CML, characterized by activated (i.e., oncogenic) protein tyrosine kinases. The combination may be used also, for example, for the treatment of epithelial tumors, such as tumors of the breast, prostate, colon, pancrease and gastric tract.

According to another preferred embodiment of the invention, the therapeutic combination comprises one or more antisense oligonucleotides specific for a raf oncogene in combination with one or more antisense oligonucleotides specific for a jun gene. The combination is used for the treatment of the aforesaid tumors of epithelial origin. In yet another preferred embodiment; ras or raf antisense oligonucleotides are combined with myc antisense oligonucleotides, particularly c-myc, for the treatment of leukemia, particularly Ph ¹ -positive leukemias. Other combinations may be adopted for treatment of yet other neoplastic diseases.

The following oncogene or proto-oncogene nucleotide sequences are set forth herein:

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c-jun SEQ ID NO:13 c-H-ras SEQ ID NO:14 c-K-ras SEQ ID NO:15 c-N-ras SEQ ID NO:16 c-raf SEQ ID NO:17 EGF-1 SEQ ID NO:18 c-fms SEQ ID NO:19 c-ros SEQ ID NO:20 c-kit SEQ ID NO:21 c-met SEQ ID NO:22 c-trk SEQ ID NO:23 c-src1 SEQ ID NO:24 c-src2 SEQ ID NO:25 c-src3 SEQ ID NO:26 c-src4 SEQ ID NO:27 c-src5 SEQ ID NO:28 c-src6 SEQ ID NO:29 c-src7 SEQ ID NO:30 c-src8 SEQ ID NO:31 c-src9 SEQ ID NO:32 c-src10 SEQ ID NO:33 c-src11 SEQ ID NO:34 c-abl SEQ ID NO:35 bcr-abl SEQ ID NO:36 (b2a2 genotype) bcr-abl SEQ ID NO:37 (b3a2 genotype) bcr-abl SEQ ID NO:38 (b1a2 genotype) c-fgr SEQ ID NO:39 c-yes SEQ ID NO:40 c-myc SEQ ID NO:41 L-myc SEQ ID NO:42 c-ets SEQ ID NO:43 c-fos SEQ ID NO:44 c-myb SEQ ID NO:45 B-myb SEQ ID NO:46 c-rel SEQ ID NO:47 c-vav SEQ ID NO:48 c-ski SEQ ID NO:49 c-spi SEQ ID NO:50 cyclin D1 SEQ ID NO:51 PML/RARα SEQ ID NO:52 AML1/MTG8 SEQ ID NO:53 E2A/prl SEQ ID NO:54 ALL-1/AF-4 SEQ ID NO:55.

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In the practice of the present invention, target oncogene/proto-oncogene polynucleotides may be single-stranded or double-stranded DNA or RNA; however, single-stranded DNA or RNA targets are preferred. It is understood that the target to which the oncogene/-proto-oncogene antisense oligonucleotides of the invention are directed include allelic forms of the targeted gene and mRNA. There is substantial guidance in the literature for selecting particular sequences for antisense oligonucleotides given a knowledge of the sequence of the target polynucleotide, e.g., Peyman and Ulmann, Chemical Reviews, 90:543-584, 1990; Crooke, Ann. Rev. Pharmacal. Toxicol., 32:329-376 (1992); and Zamecnik and Stephenson, Proc. Natl. Acad. Sci., 75:280-284 (1974). Preferably, the sequences of antisense compounds are selected such that the G-C content is at least 60%. Preferred mRNA targets include the 5' cap site, tRNA primer binding site, the initiation codon site, the mRNA donor splice site, and the mRNA acceptor splice site, e.g., Goodchild et al., U.S. Pat. No. 4,806,463.

Where the target polynucleotide comprises an mRNA transcript, oligonucleotides complementary to and hybridizable with any portion of the transcript are, in principle, effective for inhibiting translation, and capable of inducing the effects herein described. It is believed that translation is most effectively inhibited by blocking the mRNA at a site at or near the initiation codon. Thus, oligonucleotides complementary to the 5'-region of mRNA transcript are preferred. Oligonucleotides complementary to the oncogene/proto-oncogene mRNA, including the initiation codon (the first codon at the 5' end of the translated portion of the transcript), or codons adjacent the initiation codon, are preferred.

While antisense oligomers complementary to the 5'-region of the oncogene/proto-oncogene mRNA transcripts are preferred, particularly the region including the initiation codon, it should be appreciated that useful antisense oligomers are not limited to those oligomers complementary to the sequences found in the translated portion of the mRNA transcript, but also includes oligomers complementary to nucleotide sequences contained in, or extending into, the 5'- and 3'-untranslated regions.

Antisense oligonucleotides of the invention may comprise any polymeric compound capable of specifically binding to a target polynucleotide by way of a regular pattern of monomer-to-nucleoside interactions, such as Watson-Crick type of base pairing, Hoogsteen or reverse Hoogsteen types of base pairing, or the like.

Antisense compounds of the invention may also contain pendent groups or moieties, either as part of or separate from the basic repeat unit of the polymer, to enhance specificity, nuclease resistance, delivery, or other property related to efficacy, e.g., cholesterol moieties, duplex intercalators such as acridine, poly-L-lysine, "end-capping" with one or more nuclease-resistant linkage groups such as phosphorothioate, and the like.

For example, it is known that enhanced lipid solubility and/or resistance to nuclease digestion results by substituting an alkyl group or alkoxy group for a phosphate oxygen in the internucleotide phosphodiester linkage to form an alkylphosphonate oligonucleoside or alkylphosphotriester oligonucleotide. Non-ionic oligonucleotides such as these are characterized by increased resistance to nuclease hydrolysis and/or increased cellular uptake, while retaining the ability to form stable complexes with complementary nucleic acid sequences. The alkylphosphonates, in particular, are stable to nuclease cleavage and soluble in lipid. The preparation of alkylphosphonate oligonucleosides is disclosed in Tso et al., U.S. Pat. No. 4,469,863.

Preferably, nuclease resistance is conferred on the antisense compounds of the invention by providing nuclease-resistant internucleosidic linkages. Many such linkages are known in the art, e.g., phosphorothioate: Zon and Geiser, Anti-Cancer Drug Design, 6:539-568 (1991); Stec et al., U.S. Pat. No. 5,151,510; Hirschbein, U.S. Pat. No. 5,166,387; Bergot, U.S. Pat. No. 5,183,885; phosphorodithioates: Marshall et al., Science, 259:1564-1570 (1993); Caruthers and Nielsen, International application PCT/US89/02293; phosphoramidates, e.g., --OP(O)(NR ¹ R ² )--O-- with R ¹ and R ² hydrogen or C ₁ -C ₃ alkyl; Jager et al., Biochemistry, 27:7237-7246 (1988); Froehler et al., International application PCT/US90/03138; peptide nucleic acids: Nielsen et al., Anti-Cancer Drug Design, 8:53-63 (1993), International application PCT/EP92/01220; methylphosphonates: Miller et al., U.S. Pat. No. 4,507,433, Ts' o et al., U.S. Pat. No. 4,469,863; Miller et al., U.S. Pat. 4,757,055; and P-chiral linkages of various types, especially phosphorothioates, Stec et al., European patent application 506,242 (1992) and Lesnikowski, Bioorganic Chemistry, 21:127-155 (1993). Additional nuclease linkages include phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phosphoranilidate, alkylphosphotriester such as methyl- and ethylphosphotriester, carbonate such as carboxymethyl ester, carbamate, morpholino carbamate, 3'-thioformacetal, silyl such as dialkyl (C ₁ -C ₆ )- or diphenylsilyl, sulfamate ester, and the like. Such linkages and methods for introducing them into oligonucleotides are described in many references, e.g., reviewed generally by Peyman and Ulmann, Chemical Reviews 90:543-584 (1990); Milligan et al., J. Med. Chem., 36:1923-1937 (1993); Matteucci et al., International application PCT/US91/06855.

Resistance to nuclease digestion may also be achieved by modifying the internucleotide linkage at both the 5' and 3' termini with phosphoroamidites according to the procedure of Dagle et al., Nucl. Acids Res. 18, 4751-4757 (1990).

Preferably, phosphorus analogs of the phosphodiester linkage are employed in the compounds of the invention, such as phosphorothioate, phosphorodithioate, phosphoramidate, or methylphosphonate. More preferably, phosphorothioate is employed as the nuclease resistant linkage.

Phosphorothioate oligonucleotides contain a sulfur-for-oxygen substitution in the internucleotide phosphodiester bond. Phosphorothioate oligonucleotides combine the properties of effective hybridization for duplex formation with substantial nuclease resistance, while retaining the water solubility of a charged phosphate analogue. The charge is believed to confer the property of cellular uptake via a receptor (Loke et al., Proc. Natl. Acad. Sci., 86, 3474-3478 (1989)).

It is understood that in addition to the preferred linkage groups, compounds of the invention may comprise additional modifications, e.g., boronated bases, Spielvogel et al., 5,130,302; cholesterol moieties, Shea et al., Nucleic Acids Research, 18:3777-3783 (1990) or Letsinger et al., Proc. Natl. Acad. Sci., 86:6553-6556 (1989); and 5-propynyl modification of pyrimidines, Froehler et al., Tetrahedron Lett., 33:5307-5310 (1992).

Preferably, antisense compounds of the invention are synthesized by conventional means on commercially available automated DNA synthesizers, e.g., an Applied Biosystems (Foster City, Calif.) model 380B, 392 or 394 DNA/RNA synthesizer. Preferably, phosphoramidite chemistry is employed, e.g., as disclosed in the following references: Beaucage and Iyer, Tetrahedron, 48:2223-2311 (1992); Molko et al., U.S. Pat. No. 4,980,460; Koster et al., U.S. Pat. No. 4,725,677; Caruthers et al., U.S. Pat. Nos. 4,415,732; 4,458,066; and 4,973,679.

In embodiments where triplex formation is desired, there are constraints on the selection of target sequences. Generally, third strand association via Hoogsteen type of binding is most stable along homopyrimidine-homopurine tracks in a double stranded target. Usually, base triplets form in T-A*T or C-G*C motifs (where "-" indicates Watson-Crick pairing and "*" indicates Hoogsteen type of binding); however, other motifs are also possible. For example, Hoogsteen base pairing permits parallel and antiparallel orientations between the third strand (the Hoogsteen strand) and the purine-rich strand of the duplex to which the third strand binds, depending on conditions and the composition of the strands. There is extensive guidance in the literature for selecting appropriate sequences, orientation, conditions, nucleoside type (e.g., whether ribose or deoxyribose nucleosides are employed), base modifications (e.g., methylated cytosine, and the like) in order to maximize, or otherwise regulate, triplex stability as desired in particular embodiments, e.g., Roberts et al., Proc. Natl. Acad. Sci., 88:9397-9401 (1991); Roberts et al., Science, 58:1463-1466 (1992); Distefano et al., Proc. Natl. Acad. Sci., 90:1179-1183 (1993); Mergny et al., Bio-chemistry, 30:9791-9798 (1992); Cheng et al., J. Am. Chem. Soc., 114:4465-4474 (1992); Beal and Dervan, Nucleic Acids Research, 20:2773-2776 (1992); Beal and Dervan, J. Am. Chem. Soc., 114:4976-4982; Giovannangeli et al., Proc. Natl. Acad. Sci., 89:8631-8635 (1992); Moser and Dervan, Science, 238:645-650 (1987); McShan et al., J. Biol. Chem., 267:5712-5721 (1992); Yoon et al., Proc. Natl. Acad. Sci., 89:3840-3844 (1992); and Blume et al., Nucleic Acids Research, 20:1777-1784 (1992).

The length of the oligonucleotide moieties is sufficiently large to ensure that specific binding will take place only at the desired target polynucleotide and not at other fortuitous sites, as explained in many references, e.g., Rosenberg et al., International application PCT/US92/05305; or Szostak et al., Meth. Enzymol, 68:419-429 (1979). The upper range of the length is determined by several factors, including the inconvenience and expense of synthesizing and purifying oligomers greater than about 30-40 nucleotides in length, the greater tolerance of longer oligonucleotides for mismatches than shorter oligonucleotides, whether modifications to enhance binding or specificity are present, whether duplex or triplex binding is desired, and the like. Usually, antisense compounds of the invention have lengths in the range of about 12 to 60 nucleotides. More preferably, antisense compounds of the invention have lengths in the range of about 15 to 40 nucleotides; and most preferably, they have lengths in the range of about 18 to 30 nucleotides.

In general, the antisense oligonucleotides used in the practice of the present invention will have a sequence which is completely complementary to a selected portion of the target polynucleotide. Absolute complementarity is not however required, particularly in larger oligomers. Thus, reference herein to a "nucleotide sequence complementary to" a target polynucleotide does not necessarily mean a sequence having 100% complementarity with the target segment. In general, any oligonucleotide having sufficient complementarity to form a stable duplex with the target (e.g. an oncogene mRNA) that is, an oligonucleotide which is "hybridizable", is suitable. Stable duplex formation depends on the sequence and length of the hybridizing oligonucleotide and the degree of complementarity with the target polynucleotide. Generally, the larger the hybridizing oligomer, the more mismatches may be tolerated. More than one mismatch probably will not be tolerated for antisense oligomers of less than about 21 nucleotides. One skilled in the art may readily determine the degree of mismatching which may be tolerated between any given antisense oligomer and the target sequence, based upon the melting point, and therefore the thermal stability, of the resulting duplex.

Preferably, the thermal stability of hybrids formed by the antisense oligonucleotides of the invention are determined by way of melting, or strand dissociation, curves. The temperature of fifty percent strand dissociation is taken as the melting temperature, T _m , which, in turn, provides a convenient measure of stability. T _m measurements are typically carried out in a saline solution at neutral pH with target and antisense oligonucleotide concentrations at between about 1.0-2.0 μM. Typical conditions are as follows: 150 mM NaCl and 10mM MgCl ₁₂ in a 10 mM sodium phosphate buffer (pH 7.0) or in a 10mM Tris-HCl buffer (pH 7.0). Data for melting curves are accumulated by heating a sample of the antisense oligonucleotide/target polynucleotide complex from room temperature to about 85°-° C. As the temperature of the sample increases, absorbance of 260 nm light is monitored at 1° C. intervals, e.g., using a Cary (Australia) model 1E or a Hewlett-Packard (Palo Alto, Calif.) model HP 8459 UV/VIS spectrophotometer and model HP 89100A temperature controller, or like instruments. Such techniques provide a convenient means for measuring and comparing the binding strengths of antisense oligonucleotides of different lengths and compositions.

Pharmaceutical compositions of the invention include a pharmaceutical carrier that may contain a variety of components that provide a variety of functions, including regulation of drug concentration, regulation of solubility, chemical stabilization, regulation of viscosity, absorption enhancement, regulation of pH, and the like. The pharmaceutical carrier may comprise a suitable liquid vehicle or excipient and an optional auxiliary additive or additives. The liquid vehicles and excipients are conventional and commercially available. Illustrative thereof are distilled water, physiological saline, aqueous solutions of dextrose, and the like. For water soluble formulations, the pharmaceutical composition preferably includes a buffer such as a phosphate buffer, or other organic acid salt, preferably at a pH of between about 7 and 8. For formulations containing weakly soluble antisense compounds, micro-emulsions may be employed, for example by using a nonionic surfactant such as polysorbate 80 in an amount of 0.04-0.05% (w/v), to increase solubility. Other components may include antioxidants, such as ascorbic acid, hydrophilic polymers, such as, monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, dextrins, chelating agents, such as EDTA, and like components well known to those in the pharmaceutical sciences, e.g., Remington's Pharmaceutical Science, latest edition (Mack Publishing Company, Easton, Pa.).

Antisense compounds of the invention include the pharmaceutically acceptable salts thereof, including those of alkaline earths, e.g., sodium or magnesium, ammonium or NX ₄ ⁺ , wherein X is C ₁ -C ₄ alkyl. Other pharmaceutically acceptable salts include organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic, and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, and benzenesulfonic; and inorganic acids such as hydrochloric, sulfuric, phosphoric, and sulfamic acids. Pharmaceutically acceptable salts of a compound having a hydroxyl group include the anion of such compound in with a suitable cation such as Na ⁺ , NH ₄ ⁺ , or the like.

The antisense oligonucleotides are preferably administered parenterally, most preferably intravenously. The vehicle is designed accordingly. Alternatively, oligonucleotide may be administered subcutaneously via controlled release dosage forms.

In addition to administration with conventional carriers, the antisense oligonucleotides may be administered by a variety of specialized oligonucleotide delivery techniques. Sustained release systems suitable for use with the pharmaceutical compositions of the invention include semi-permeable polymer matrices in the form of films, microcapsules, or the like, comprising polylactides; copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, poly(2-hydroxyethyl methacrylate), and like materials, e.g., Rosenberg et al., International application PCT/US92/05305.

The oligonucleotides may be encapsulated in liposomes for therapeutic delivery, as described for example in Liposome Technology, Vol. II, Incorporation of Drugs, Proteins, and Genetic Material, CRC Press. The oligonucleotide, depending upon its solubility, may be present both in the aqueous layer and in the lipidic layer, or in what is generally termed a liposomic suspension. The hydrophobic layer, generally but not exclusively, comprises phospholipids such as lecithin and sphingomyelin, steroids such as cholesterol, ionic surfactants such as diacetylphosphate, stearylamine, or phosphatidic acid, and/or other materials of a hydrophobic nature.

The oligonucleotides may be conjugated to poly(L-lysine) to increase cell penetration. Such conjugates are described by Lemaitre et al., Proc. Natl. Acad. Sci. USA , 84, 648-652 (1987). The procedure requires that the 3'-terminal nucleotide be a ribonucleotide. The resulting aldehyde groups are then randomly coupled to the epsilon-amino groups of lysine residues of poly(L-lysine) by Schiff base formation, and then reduced with sodium cyanoborohydride. This procedure converts the 3'-terminal ribose ring into a morpholine structure antisense oligomers.

Antisense compounds of the invention also include conjugates of such oligonucleotides with appropriate ligand-binding molecules. The oligonucleotides may be conjugated for therapeutic administration to ligand-binding molecules which recognize cell-surface molecules, such as according to International Patent Application WO 91/04753. The ligand-binding molecule may comprise, for example, an antibody against a cell surface antigen, an antibody against a cell surface receptor, a growth factor having a corresponding cell surface receptor, an antibody to such a growth factor, or an antibody which recognizes a complex of a growth factor and its receptor. Methods for conjugating ligand-binding molecules to oligonucleotides are detailed in WO 91/04753.

In particular, the growth factor to which the antisense oligonucleotide may be conjugated, may comprise transferrin or folate. Transferrin-polylysine-oligonucleotide complexes or folate-polylysine-oligonucleotide complexes may be prepared for uptake by cells expressing high levels of transferrin or folate receptor. The preparation of transferrin complexes as carriers of oligonucleotide uptake into cells is described by Wagner et al ., Proc. Natl. Acad. Sci. USA 87, 3410-3414 (1990). Inhibition of leukemia cell proliferation by transferrin receptor-mediated uptake of c-myb antisense oligonucleotides conjugated to transferrin has been demonstrated by Citro et al., Proc. Natl. Acad. Sci. USA ., 89, 7031-7035 (1992). Cellular delivery of folate-macromolecule conjugates via folate receptor endocytosis, including delivery of an antisense oligonucleotide, is described by Low et al., U.S. Pat. No. 5,108,921. Also see, Leamon et al., Proc. Natl. Acad. Sci. 88, 5572 (1991).

A preferred method of administration of oligonucleotides comprises either systemic or regional perfusion, as is appropriate. According to a method of regional perfusion, the afferent and efferent vessels supplying the extremity containing the lesion are isolated and connected to a low-flow perfusion pump in continuity with an oxygenator and a heat exchanger. The iliac vessels may be used for perfusion of the lower extremity. The axillary vessels are cannulated high in the axilla for upper extremity lesions. Oligonucleotide is added to the perfusion circuit, and the perfusion is continued for an appropriate time period, e.g., one hour. Perfusion rates of from 100 to 150 ml/minute may be employed for lower extremity lesions, while half that rate should be employed for upper extremity lesions. Systemic heparinization may be used throughout the perfusion, and reversed after the perfusion is complete. This isolation perfusion technique permits administration of higher doses of chemotherapeutic agent than would otherwise be tolerated upon infusion into the arterial or venous systemic circulation.

For systemic infusion, the oligonucleotides are preferably delivered via a central venous catheter, which is connected to an appropriate continuous infusion device. Indwelling catheters provide long term access to the intravenous circulation for frequent administration of drugs over extended time periods. They are generally surgically inserted into the external cephalic or internal jugular vein under general or local anesthesia. The subclavian vein is another common site of catheterization. The infuser pump may be external, or may form part of an entirely implantable central venous system such as the INFUSAPORT system available from Infusaid Corp., Norwood, Mass. and the PORT-A-CATH system available from Pharmacia Laboratories, Piscataway, N.J. These devices are implanted into a subcutaneous pocket under local anesthesia. A catheter, connected to the pump injection port, is threaded through the subclavian vein to the superior vena cava. The implant contains a supply of oligonucleotide in a reservoir which may be replenished as needed by injection of additional drug from a hypodermic needle through a self-sealing diaphragm in the reservoir. Completely implantable infusers are preferred, as they are generally well accepted by patients because of the convenience, ease of maintenance and cosmetic advantage of such devices.

As an alternative to treatment with exogenous oligonucleotides, antisense polynucleotide synthesis may be induced in situ by local treatment of the targeted neoplastic cells with a vector containing an artificially-constructed gene comprising transcriptional promotors and targeted oncogene/proto-oncogene DNA in inverted orientation. The DNA for insertion into the artificial gene in inverted orientation comprises cDNA which may be prepared, for example, by reverse transcriptase polymerase chain reaction from RNA using primers derived from the published target oncogene/proto-oncogene cDNA sequences.

A first DNA segment for insertion contains cDNA of a cytoplasmic oncogene/proto-oncogene. A second DNA segment for insertion contains cDNA of a nuclear oncogene/proto-oncogene. The two segments are under control of corresponding first and second promotor segments. Upon transcription, the inverted oncogene/proto-oncogene segments, which are complementary to the corresponding targeted oncogene/proto-oncogenes, are produced in situ in the targeted cell. The endogenously produced RNAs hybridize to the relevant oncogene/proto-oncogene mRNAs, resulting in interference with oncogene function and inhibition of the proliferation of the targeted cell.

The promotor segments of the artificially-constructed gene serve as signals conferring expression of the inverted oncogene/proto-oncogene sequences which lie downstream thereof. Each promotor will include all of the signals necessary for initiating transcription of the relevant downstream sequence. Each promotor may be of any origin as long as it specifies a rate of transcription which will produce sufficient antisense mRNA to inhibit the expression of the target oncogene/proto-oncogene, and therefore the proliferation of the targeted cells. Preferably, a highly efficient promotor such as a viral promotor is employed. Other sources of potent promotors include cellular genes that are expressed at high levels. The promotor segment may comprise a constitutive or a regulatable promotor.

The artificial gene may be introduced by any of the methods described in U.S. Pat. No. 4,740,463, incorporated herein by reference. One technique is transfection; which can be done by several different methods. One method of transfection involves the addition of DEAE-dextran to increase the uptake of the naked DNA molecules by a recipient cell. See McCutchin, J. H. and Pagano, J. S., J. Natl. Cancer Inst. 41, 351-7 (1968). Another method of transfection is the calcium phosphate precipitation technique which depends upon the addition of Ca ⁺ + to a phosphate-containing DNA solution. The resulting precipitate apparently includes DNA in association with calcium phosphate crystals. These crystals settle onto a cell monolayer; the resulting apposition of crystals and cell surface appears to lead to uptake of the DNA. A small proportion of the DNA taken up becomes expressed in a transfectant, as well as in its clonal descendants. See Graham, F. L. and van der Eb, A. J., Virology 52, 456-467 (1973) and Virology 54, 536-539 (1973).

Transfection may also be carried out by cationic phospholipid-mediated delivery. In particular, polycationic liposomes can be formed from N- 1-(2,3-di-oleyloxy)propyl!-N,N,N-trimethylammonium chloride (DOT-MA). See Felgner et al., Proc. Natl. Acad. Sci., 84, 7413-7417 (1987) (DNA-transfection); Malone et al., Proc. Natl. Acad. Sci., 86, 6077-6081 (1989) (RNA-transfection).

Alternatively, the artificially-constructed gene can be introduced in to cells, in vitro or in vivo, via a transducing viral vector. See Tabin et al., Mol. Cel. Biol. 2,426-436 (1982). Use of a retrovirus, for example, will infect a variety of cells and cause the artificial gene to be inserted into the genome of infected cells. Such infection could either be accomplished with the aid of a helper retrovirus, which would allow the virus to spread through the organism, or the antisense retrovirus could be produced in a helper-free system, such as Ψ2 like cells (See Mann et al., Cell 33, 153-160, 1983) that package amphotropic viruses. A helper-free virus might be employed to minimize spread throughout the organism. Viral vectors in addition to retroviruses can also be employed, such as papovaviruses, SV40-like viruses, or papilloma viruses. The use of retroviruses for gene transfer has been reviewed by Eglitis and Anderson, BioTechniques 6, 608-614 (1988).

Vesicle fusion could also be employed to deliver the artificial gene. Vesicle fusion may be physically targeted to the malignant cells if the vesicle were approximately designed to be taken up by those cells. Such a delivery system would be expected to have a lower efficiency of integration and expression of the artificial gene delivered, but would have a higher specificity than a retroviral vector. A strategy of targeted vesicles containing papilloma virus or retrovirus DNA molecules might provide a method for increasing the efficiency of expression of targeted molecules.

Particulate systems and polymers for in vitro and in vivo delivery of polynucleotides were extensively reviewed by Felgner in Advanced Drug Delivery Reviews 5, 163-187 (1990). Techniques for direct delivery of purified genes in vivo, without the use of retroviruses, has been reviewed by Felgner in Nature 349, 351-352 (1991). Such methods of direct delivery of polynucleotides may be utilized for local delivery of either exogenous oncogene antisense oligonucleotide or artificially-constructed genes producing oncogene antisense oligonucleotide in situ.

Recently, Wolf et al. demonstrated that direct injection of non-replicating gene sequences in a non-viral vehicle is possible. See Science, 247, 1465-1468 (1990). DNA injected directly into mouse muscle did not integrate into the host genome, and plasmid essentially identical to the starting material was recovered from the muscle months after injection. Interestingly, no special delivery system is required. Simple saline or sucrose solutions are sufficient to delivery DNA and RNA.

The antisense oligonucleotides may be used as the primary therapeutic for the treatment of the disease state, or may be used in with non-oligonucleotide agents. In particular, the antisense oligonucleotides may find utility as bone marrow purging agents in the treatment of leukemias or cancers which have metastasized to the bone marrow. High dose chemotherapy coupled with autologous bone marrow rescue involves removing a portion of the patient's bone marrow, treating the patient with conventional chemotherapy or radiation to substantially destroy the remaining malignant bone marrow cells, treating the stored bone marrow with an agent to eradicate neoplastic cells, and returning the treated cells to the patient. The treated cells, when returned to the patient, may be stimulated by various known hematopoietic growth factors to repopulate the bone marrow with cells which do not carry the oncogenic transcript.

According to a method for bone marrow purging, bone marrow is harvested from a donor by standard operating room procedures from the iliac bones of the donor. Methods of aspirating bone marrow from donors are well-known in the art. Examples of apparatus and processes for aspirating bone marrow from donors are disclosed in U.S. Pat. Nos. 4,481,946 and 4,486,188. Sufficient marrow is withdrawn so that the recipient, who is either the donor (autologous transplant) or another individual (allogeneic transplant), may receive from about 4×10 ⁸ to about 8×10 ⁸ processed marrow cells per kg of bodyweight. This generally requires aspiration of about 750 to about 1000 ml of marrow. The aspirated marrow is filtered until a single cell suspension, known to those skilled in the art as a "buffy coat" preparation, is obtained. This suspension of leukocytes is treated with the relevant antisense oligonucleotides in a suitable carrier, advantageously in a concentration of about 50-200 μg/ml. Alternatively, the leucocyte suspension may be stored in liquid nitrogen using standard procedures known to those skilled in the art until purging is carried out. The purged marrow can be stored frozen in liquid nitrogen until ready for use. Methods of freezing bone marrow and biological substances are disclosed, for example, in U.S. Pat. Nos. 4,107,937 and 4,117,881.

Other methods of preparing bone marrow for treatment with antisense oligonucleotide may be utilized, which methods may result in even more purified preparations of hematopoietic cells than the aforesaid buffy coat preparation.

While hematopoietic growth factors are typically added to the aspirated marrow or buffy coat preparation to stimulate growth of hematopoietic neoplasms, the amount of growth factor added in the practice of the present invention should be limited to only what is necessary to sustain the normal cell population. If too much growth factor is added, differential sensitivity to antisense inhibition as between normal and leukemic cells in the aspirated marrow may be lost. One skilled in the art may readily determine the appropriate amount of growth factor. Growth factors, if used, may include, for example, IL-3 and granulocyte macrophage colony stimulating factor (GM-CSF). The recombinant human versions of such growth factors are advantageously employed.

After treatment with the antisense oligonucleotides, the cells to be transferred are washed with autologous plasma or buffer to remove unincorporated oligomer. The washed cells are then infused back into the patient. Other methods for bone marrow purging utilizing antisense oligonucleotide are disclosed in U.S. Pat. No. 5,087,617.

According to a preferred treatment regimen for bone marrow purging, the aspirated bone marrow is contacted daily or twice daily for approximately one to four days with an amount of antisense oligonucleotides effective to overcome the malignant phenotype.

For systemic or regional in vivo administration, the amount of antisense oligonucleotides may vary depending on the nature and extent of the neoplasm, the particular oligonucleotides utilized, and other factors. The actual dosage administered may take into account the size and weight of the patient, whether the nature of the treatment is prophylactic or therapeutic in nature, the age, health and sex of the patient, the route of administration, whether the treatment is regional or systemic, and other factors. Intercellular concentrations of from about 1 to about 200 μg/ml at the target polynucleotide may be employed, preferably from about 10 μg/ml to about 100 μg/ml. The patient should receive a sufficient daily dosage of antisense oligonucleotide to achieve these intercellular concentrations of combined oligonucleotides. The daily combined oligonucleotide dosage combination of nuclear and cytoplasmic oncogene/proto-oncogene-targetting oligonucleotides may range from about 25 mg to about 2 grams per day, with at least about 250 mg being preferred. An effective human continuous intravenous infusion dosage, based upon animal studies employing antisense oligonucleotides targeting other genes in antileukemic therapy, is about 0.4 mg/kg/day. Greater or lesser amounts of oligonucleotide may be administered, as required. Those skilled in the art should be readily able to derive appropriate dosages and schedules of administration to suit the specific circumstance and needs of the patient. It is believed that a course of treatment may advantageously comprise infusion of the recommended daily dose as a continuous intravenous infusion over 7 days. The oligonucleotides may be given for a period of from about 3 to about 28 days, more preferably from about 7 to about 10 days. Those skilled in the art should readily be able to determine the optimal dosage in each case. For modified oligonucleotides, such as phosphorothioate oligonucleotides, which have a half life of from 24 to 48 hours, the treatment regimen may comprise dosing on alternate days.

The ratio of the amounts of cytoplasmic gene-specific to nuclear gene-specific antisense oligonucleotide may vary over a broad range. Preferably, the ratio varies from about 10:1 to about 1:10, by weight, more preferably from about 4:1 to about 1:4, most preferably from about 3:1 to about 1:3. According to one preferred embodiment of the invention, the two oligonucleotides are present in approximately equal amounts, by weight. Of course, it may be appreciated that where plural cytoplasmic oncogene-specific oligonucleotides and/or plural nuclear oncogene-specific oligonucleotides are utilized, the total weight of lo all such compounds is considered with respect to the aforementioned preferred cytoplasmic/nuclear antisense ratio.

For ex vivo antineoplastic application, such as, for example, in bone marrow purging, the antisense oligonucleotides may be administered in amounts effective to kill neoplastic cells. Such amounts may vary depending on the extent to which malignant cells may arise in or have metastasized to the bone marrow, the particular oligonucleotide utilized, the relative sensitivity of the neoplastic cells to the oligonucleotide, and other factors. Total oligonucleotide concentrations from about 10 to 200 μg/ml per 10 ⁵ cells may be employed, preferably from about 40 to 150 μg/ml per 10 ⁵ cells. Supplemental dosing of the same or lesser amounts of oligonucleotide are advantageous to optimize the treatment. Thus, for purging bone marrow containing 2×10 ⁷ cell per ml of marrow volume, dosages of from about 2 to 40 mg antisense per ml of marrow may be effectively utilized, preferably from about 8 to 24 mg/ml. Greater or lesser amounts of oligonucleotide may be employed.

The effectiveness of the treatment may be assessed by routine methods which are used for determining whether or not remission has occurred. Such methods generally depend upon some of morphological, cytochemical, cytogenetic, immunologic and molecular analyses. In addition, remission can be assessed genetically by probing the level of expression of one or more relevant oncogenes. The reverse transcriptase polymerase chain reaction methodology can be used to detect even very low numbers of mRNA transcript. For example, RT-PCR has been used to detect and genotype the three known bcr-abl fusion sequences in Ph ¹ leukemias. See PCT/US9-2/05035 and Kawasaki et al., Proc. Natl. Acad. Sci. USA 85, 5698-5702 (1988).

Typically, therapeutic success is assessed by the decrease and the extent of the primary and any metastatic diseases lesions. For solid tumors, decreasing tumor size is the primary indicia of successful treatment. Neighboring tissues should be biopsied to determine the extent to which metastasis has occurred. Tissue biopsy methods are known to those skilled in the art. For non-solid tumors, i.e. the leukemias, treatment is monitored primarily by histological examination of the bone marrow for surviving leukemic cells. However, a significant number of leukemic cells may still exist when marrow examination provides normal results. For this reason, more recent methods for detecting leukemic cells have focused on detecting the presence of the gene for the relevant oncogene, or its corresponding mRNA, in cells of the bone marrow as a more sensitive test. See, for example, the following U.S. Pat. Nos. 4,681,840, 4,857,466 and 4,874,853. The presence of even a few copies of the target oncogene can be effectively detected by amplification using reverse transcriptase polymerase chain reaction technology. For a detailed discussion of such methods, see for example, Cancer: Principles & Practice of Oncology, edited by V. T. DeVita, S. Hellman and S. A. Rosenberg, J. B. Lippincott Company, Philadelphia, Pa. (3rd ed., 1989). Methods for diagnosing and monitoring the progress of neoplastic disorders vary depending upon the nature of the particular disease.

An antileukemic treatment plan is proposed as follows. Antisense oligonucleotides (phosphorothioate 24-mer) are administered as a 24-hour continuous intravenous infusion over 7 days. Each oligonucleotide is placed in 5% dextrose water and given at a daily dose ranging from about 0.30 to about 2 mg/kg/day. The dosage may be escalated as needed. Bone marrow aspiration/biopsy is conducted 7, 14 and 21 days after the first cycle of therapy. The patient is evaluated for response on day 21. Additional cycles of therapy may be performed. For such additional cycles of therapy, a bone marrow biopsy will be performed 21 days after the initiation of therapy. Complete remission is determined by the presence of all of the following for a period of at least 4 weeks: (1) a white count below 10,000/mm ³ with granulocytes >1,000/mm ³ ; (2) platelet count of ≥100,000/mm ³ ; (3) absence of leukemic blasts from the peripheral blood; (4) a cellularity of bone marrow biopsy of≥20%, with maturation of all cell lines; (5)≥5% blasts in the bone marrow; (6) the absence of detectable Auer rods; (7) the absence of organomegaly; (8) the absence of extramedullary leukemia, such as central nervous system or soft tissue involvement.

According to one preferred embodiment, the invention comprises in vivo or ex vivo treatment of Ph ¹ -positive leukemias, that is, leukemias characterized by the chromosomal abnormality known as the Philadelphia or Ph ¹ chromosome. At the molecular level, the most notable feature is the translocation of the proto-oncogene c-abl from the long arm of chromosome 9 to the breakpoint cluster region (bcr) on chromosome 22, resulting in the formation of bcr-abl hybrid genes. The break occurs near the end of the long arm of chromosome 9 (band 9q34) and in the upper half of chromosome 22 (band 22q11).

The c-abl proto-oncogene normally encodes a protein with tyrosine kinase activity. This activity is augmented in cells carrying bcr-abl hybrid genes. The gene located at the breakpoint on chromosome 22 is called bcr because the break in chromosome 22 in CML occurs in a very small 5.8-kilobase (kb) segment (breakpoint cluster region) of the gene on chromosome 22. Two alternative first exons of the c-abl oncogene exist, namely exon 1a and exon 1b, which are spliced to the common splice acceptor site, exon 2. As a result of this configuration, at least two major c-abl messages are transcribed, differing in their 5' regions. (Shtivelman et al., Cell 47, 277 (1986); Bernards et al., Mol. Cell. Biol. 7, 3231 (1987); Fainstein et al., Oncogene4, 1477-1481 (1989)). If exon 1b is used, the mRNA is 7.0 kb. If exon 1a is used, the mRNA is 6.0 kb. Each of exons 1a and 1b are preceded by a transcriptional promotor. The 9;22 translocation in CML results in the abnormal juxtaposition of abl sequences adjacent to bcr sequences. The fusion leads to an 8.5 kb chimeric mRNA consisting of 5' BCR sequences and 3' abl sequences. The chimeric message is in turn translated into a larger chimeric abl protein (210 kDa) that has increased tyrosine kinase activity (Konopka et al., Cell 37, 1035 (1984); Kloetzer et al., Virology140, 230 (1985).

Two major types of bcr-abl translocations are known, characterized by two different bcr-abl junctions. One translocation is between bcr exon 2 and abl exon 2, while another translocation is between bcr exon 3 and the same abl exon 2 (Shtivelman et al., Cell 47, 277-284 (1986)). The two types of junction have been referred to as the "L-6" (or "b2a2") and "K-28" (or "b3a2") junctions, respectively. The alternative splicing from two bcr-abl exons to the abl coding sequence results in two different bcr-abl fusion proteins, one including the 25 amino acids encoded by bcr exon 3 and one which lacks those amino acids. One or both of these junctions is detected in Ph ¹ -positive CML patients (Shtivelman et al., Blood 69, 971 (1986)).

A significant portion of acute lymphocytic leukemia (ALL) patients carry Ph ¹ chromosomes in their leukemic cells. Ph ¹ -positive ALL is generally regarded as being less responsive to chemotherapeutic treatment than Ph ¹ -negative forms of ALL. This is particularly true of children with Ph ¹ -positive ALL.

Approximately one half of Ph ¹ -positive individuals afflicted with ALL express either of the two major bcr-abl junctions, L-6 or K-28. The remainder have bcr-abl genes characterized by a junction formed by the fusion of bcr exon 1 and c-abl exon 2 ("bla2" junction). See Fainstein et al., Nature 330, 386-388 (1987).

Clinically, CML invariably progresses from the chronic phase into the blast crisis. In chronic phase CML, the increase in mature and immature myeloid elements in bone marrow and peripheral blood is the most characteristic feature (Koeffler et al., N. Engl. J. Med. 304, 201 (1981)). Kinetic studies indicate that these abnormal cells do not proliferate or mature faster than their normal counterparts. Instead, the basic defect underlying the exuberant granulopoiesis in CML appears to reside in the expansion of the myeloid progenitor cell pool in bone marrow and peripheral blood. Id. Nevertheless, the generation of terminally differentiated cells indicates that the process of hematopoiesis retains some normal features. In contrast, during blastic transformation, the leukemic cells exhibit a marked degree of differentiation arrest with a "blast" phenotype (Rosenthal et al., Am. J. Med. 63, 542 (1977)). The onset of the blastic transformation or "blast crisis" limits the therapeutic options available. The disease-free period, and consequently survival, is generally brief. Typically it is less than about four months.

According to a preferred embodiment of the practice of the present invention, phi-positive leukemias are treated, either in vivo or ex vivo, with a combination of antisense oligonucleotides. Preferably, the oligonucleotides comprise at least one bcr-abl-specific antisense oligonucleotide, and at least one antisense oligonucleotide specific for a nuclear oncogene or proto-oncogene.

Preferably, the bcr-abl antisense oligonucleotide is complementary to a position of the bcr-abl mRNA corresponding to the breakpoint junction between the bcr-derived and abl-derived portions of the mRNA. By "abl-derived portion" is meant that portion of the bcr-abl RNA transcript which results from the transcription of the abl coding sequence which is translocated to the bcr coding sequence in the chromosomal translocation event giving rise to formation of the Ph ¹ chromosome. Similarly, by "bcr-derived portion" of the bcr-abl transcript is meant that portion which results from the transcription of the bcr coding sequence which is juxtaposed to c-abl. This ensures specific hybridization to bcr-abl transcripts. Most preferably, the antisense molecule is complementary to a target mRNA sequence containing an about equal number of abl-derived nucleotides and bcr-derived nucleotides, that is, an about equal number of nucleotides on either side flanking the translocation breakpoint. Preferred antisense oligonucleotides complementary to the bcr-abl b1a2, b2a2 and b3a2 junctions are disclosed in International Patent Application W092/22303, the disclosure of which is incorporated herein by reference.

The practice of the present invention is illustrated by the following non-limiting examples. Combinations of nuclear and cytoplasmic oligonucleotides were more effective than either oligonucleotide alone.

EXAMPLE 1

Effect of bcr-abl and c-myc Antisense Oligonucleotides on BV-173 Cells

A. Phosphorothioate Oligodeoxynucleotides

Phosphorothioate oligodeoxynucleotides ( S!ODNs ) were synthesized on an Applied Biosystems model 390Z automated synthesizer. The sequence of the b2/a2 bcr-abl antisense S!ODN CGCTGAAGGG CTTCTTCCTT ATTGAT (SEQ ID NO:1) was complementary to a 26-nucleotide segment of the bcr-abl mRNA transcript spanning thirteen nucleotides upstream and downstream of the c-abl exon 2 and BCR exon 2 breakpoint junction. The sequence of the c-myc antisense S!ODN TTGGTGAAGC TAACGTTGAG GGGCAT (SEQ ID NO:3) was complementary to the first 26 nucleotides of the mRNA transcript beginning from the translation initiation codon. Corresponding sense oligonucleotides had the sequences ATCAATAAGG AAGAAGCCCT TCAGCG (bcr-abl, SEQ ID NO:2) and ATGCCCCTCA ACGTTAGCTT CACCAA (c-myc, SEQ ID NO:4).

B. Cell Proliferation Assay

Chronic myelogenous leukemia (BV173) cells (10 ⁴ /100 μl/well) were placed in 96-well culture plates in RPMI medium supplemented with 10% fetal bovine serum, L-glutamine, and penicillin/streptomycin. For the protein studies and cell cycle analysis described below, 5×10 ⁶ BV173 cells/20 ml of medium were placed in 175 cm ² LUX tissue culture flasks (Nunc, Inc., Naperville, Ill.). Sense or antisense S! ODNs were added at the beginning of culture and again (at 50% of the initial dose) 24 and 48 hours later. The final concentrations of S! ODNs are indicated in FIG. 1A (10 μg/ml), FIG. 1B (5 μg/ml) and FIG. 1C (2.5 μg/ml). Control cells were left untreated. Cells in 96-well plates were counted in Trypan blue on days +4,+6 and +8. Cells in flasks were centrifuged on HISTOPAQUE-1077, washed, counted and used for further studies. The results are shown in FIGS. 1A-1C: (.largecircle.) control; (Δ) b2/a2 plus c-myc sense; (.quadrature.) b2/a2 antisense; (.box-solid.) c-myc antisense, (.circle-solid.) b2/a2 and c-myc antisense.

C. Protein Analysis

In this experiment, total cellular proteins were isolated from BV 173 cells after 72 hours of incubation without S! ODNs (control), or with 10 μg/ml of the above indicated S! ODNs and analyzed by SDS-PAGE and Western blotting for the expression of indicated proteins. Accordingly, 10 ⁶ cells were solubilized in RIPA lysis buffer containing 10% deoxycholate, 2% NP-40, 02% SDS, and 10% glycerol, in Tris-buffered saline, pH 7.2. Proteins were separated on 7.5% SDS-PAGE and transferred to nitrocellulose (MCI, Westboro, Mass.). Filters were blocked in 0.5% gelatin in TBS and then incubated with murine monoclonal anti-ABL antibody (gift of Dr. R. Arlinghaus, M. D. Anderson Medical Center, Houston, Tex.), murine monoclonal anti-c-MYC antibody (Oncogene Science Inc., Uniondale, N.J.), and murine monoclonal anti-HSP 72/72 (Oncogene Science). Filters were washed 5 times with 0.2% TWEEN 0.25% NP-40 in TBS buffer and blotted with anti-murine polyclonal antibody linked to horseradish peroxidase (Amersham Corp., Arlington Heights, Ill.). Proteins were detected using the ECL Western blotting system (Amersham). The results are shown in FIG. 2.

D. Cell Cycle Analysis

After incubation for 24, 48, and 72 hours in the presence of antisense S! ODNs (b2/a2, 10 μg/ml; c-myc 10 μg/ml; b2/a2, 2.5 μg/ml; b2/a2+c-myc, 2.5 μg/ml), DNA content of BV173 cells was determined by flow cytometry. Cells (10 ⁶ ) were fixed in 70% ethanol for 15 minutes at 4° C., washed and incubated in 1 ml of PBS+0.1% NP-40+1 mg/ml of DNAse-free RNAse (Boehringer Mannheim Co., Indianapolis, Ind.) for 10 minutes at room temperature. Propidium iodide (5 μg/ml) was added and cells were analyzed by the EPICS PROFILE analyzer (Coulter). The results are shown in FIGS. 3A-3D for the following concentrations of the following antisense S! ODNs : 3A, b2/a2 10 μg/ml; 3B, c-myc 1 μg/ml, 3C, b2/a2 2.5 μg/ml; 3D, b2/a2+c-myc 2.5 μg/ml.

E. Discussion

In vitro proliferation of Philadelphia ¹ -positive BV173 cells which carry the bcr exon 2-abl exon 2 (b2/a2) junction was completely inhibited in the presence of b2/a2 or c-myc antisense oligodeoxynucleotides at a concentration of 10 μg/ml each (FIG. 1A-1C), whereas the S! ODNs inhibited proliferation at a 2-and 4-fold lower final concentration, i.e., concentrations at which the individual S! ODNs were nearly or completely ineffective (FIG. 1A-1C). Sense S! ODNs were non-inhibitory at any concentration tested.

Inhibition of BV173 cell proliferation by b2/a2 or c-myc antisense S! ODNs was accompanied by a down-regulation of bcr/abl and c-MYC protein levels, respectively (FIG. 2). Expression of MYC protein was also partially inhibited by b2/a2 antisense S! ODNs , which might rest in a functional linkage between bcr/abl and c-myc. The combined treatment with b2/a2+c-myc antisense S! ODNs downregulated both BCR/ABL and c-MYC protein expression. In this case downregulation of c-MYC proteins appears more pronounced than that obtained using the individual antisense S! ODNs .

Analysis of cellular DNA content (cell cycle distribution) by flow cytometry revealed that treatment with b2/a2 or c-myc antisense S! ODNs , as well as with the of both antisense S! ODNs at concentrations affecting their proliferation, led after 48 and 72 hours to accumulation of cells in S phase of the cell cycle, concomitant with a decrease in the proportion of G1 and G2 cells, and with the appearance of cells with fractional DNA content (FIGS. 3A-3D). The changes in the cell cycle, when analyzed in light of the suppressed cell proliferation by antisense S! ODNs treatment (FIGS. 1A-1C), indicate a dramatically slowed cell progression through S phase. The cells with fractional DNA content are typical of cells dying by mode of apoptosis. The degraded, low molecular weight DNA from apoptotic cells is generally extracted prior to and during the staining procedure. Such cells, as well as apoptotic bodies, stain with much lower intensity with DNA fluorochromes, representing a "sub-G1" cell population on the DNA frequency histograms. This population is very heterogeneous with respect to DNA content, both after 48 and 72 hours (FIGS. 3A-3D), which indicates different degrees of DNA degradation in individual cells. This in turn is suggestive that cell death in these cultures was asynchronous.

The apoptotic mode of cell death, and the asynchrony of apoptosis, were confirmed by observation of cell morphology following differential staining of DNA and protein (data not shown). The changes characteristic of apoptosis, involving cell shrinkage, chromatin condensation, fragmentation of nuclei, hyperchromicity of chromatin, and shedding of apoptotic bodies, were observed in all cultures treated with b2/a2, c-myc or of both antisense S! ODNs . After 48, and especially after 72 hours, there were numerous very late apoptotic cells in these cultures, containing very little, or almost no stainable DNA.

Thus, the flow cytometric data indicate that exposure of cells to b2/a2 or c-myc antisense S! ODNs , or to both of these S! ODNs , while not precluding cell entrance into S phase, does prevent cell progression through the S phase.

EXAMPLE 2

Effect of bcr-abl and c-myc Antisense Oligonucleotides on Growth of CML

Blast Crisis Patient Cells

Bone marrow cells collected from CML patients in blast crisis were suspended (10 ⁵ cells/0.4 ml) in Iscove's modified Dulbecco medium supplemented with 2% of human AB serum, Hepes buffer, L-glutamine and peni/strepto. The cells were treated in liquid culture for 5 days with bcr-abl, or c-myc, or bcr-abl+c-myc sense (S) or antisense (AS) S! ODNs (80 μg/ml added on day 0, 40 μg/ml on day+1, and 40 μg/ml on day+2). The S! ODNs doses were equally divided in the case of combination in liquid culture for 5 days. Then the cells were plated in methylcellulose and the colonies and clusters were counted after 7-12 days of incubation. The results shown in Table 1 represent mean±standard deviation from two experiments, each performed in duplicate.

TABLE 1

______________________________________

Synergistic effect of bcr/abl + c-myc antisense S!ODNs on the growth of CML-BC cells S!ODNs COLONIES PATIENT bcr/abl c-myc mean ± SD

______________________________________

A (b2/a2) -- -- 1365 ± 219 S S 1259 ± 85 AS -- 274 ± 31 -- AS 245 ± 26 AS AS 73 ± 21 a B (b3/a2) -- -- 954 ± 85 S S 974 ± 42 AS -- 488 ± 18 -- AS 451 ± 9 AS AS 162 ± 38 b C (b2/a2) -- -- 129 ± 16 S S 140 ± 40 AS -- 56 ± 5 -- AS 51 ± 5 AS AS 22 ± 6 c

______________________________________

^a p = 0.017, and p = 0.019 in comparison to bcrabl AS, and cmyc AS group, respectively. ^b p = 0.008, and p = 0.009 in comparison to bcrabl AS, and cmyc AS group, respectively. ^c p < 0.001 in comparison to bcrabl AS, and cmyc AS group.

EXAMPLE 3

In Vivo Effect of bcr-abl and c-myc Antisense Oligonucleotides

The antileukemic effects of bcr-abl and c-myc ODNs, alone and in combination, were assessed in vivo as follows.

A. Leukemic Cell Assay-4 Weeks Post-Transplantation of Leukemic Cells

Immunodeficient SCID mice (males 8-10 weeks old, 20-22 g) were injected intravenously with 10 ⁶ BV173 cells, a regimen that produces a disease process reminiscent of that in humans. Seven days later, mice were systemically injected for 12 consecutive days with 1 mg/day/mouse of b2/a2 sense+c-myc sense (6 days each, every other day), b2/a2 antisense, c-myc antisense or b2/a2+c-myc antisense (6 days each, every other day). Control mice were injected with diluent only. Four weeks after leukemia implantation, peripheral blood (PBL), spleen (SPL), and bone marrow (BMC) from one mouse per group were analyzed to assess the disease process. Leukemia growth in the mice was analyzed by assessing the tissues for CD1O+cells by immunocytometry and for clonogenic growth in methylcellulose as described by Skorski et al., Proc. Natl. Acad. Sci. USA 91:4504 (1994). Immunofluorescence assay (sensitivity 10 ^-2 ) did not detect CD10+leukemic cells, whereas colony assay (sensitivity 10 ^-3 ) revealed several clonogenic leukemia cells in BMC suspensions of control and sense S! ODNs -treated mice, but none from cell suspensions of mice treated with antisense S! ODNs either individually or in combination (not shown). RT-PCR amplification of bcr-abl transcripts present in the total RNA isolated from bone marrow and spleen, followed by Southern blot hybridization, revealed a relatively strong signal from amplification products of RNA isolated from control and sense S! ODNs -treated mice, but only a weak signal in RNA derived from tissue of mice treated with individual ODNs, and a nearly undetectable signal in RNA from the mouse treated with both b2/a2+c-myc antisense S! ODNs (not shown). Equal amounts of β-actin transcript were detected in RNA samples from each tissue.

B. Leukemic Cell Assay--8 Weeks Post-Transplantation of Leukemic Cells

Mice were inoculated intravenously with 10 ⁶ BV173 cells and 7 days later, injected i.v. with sense (S) or antisense (AS) S! ODNs (1 mg/mouse/day) for 12 consecutive days. In the group (b2/a2+c-myc) S! ODNs were injected every other day. Control mice were injected with diluent only. Leukemia growth in the mice was analyzed on day 56 by assessing peripheral blood leukocytes (PBL), spleen (SPL), and bone marrow cells (BMC) for CD10+cells by immunocytometry and for clonogenic growth in methylcellulose. The results are given in Table 2. Numbers show individual results obtained from 3 mice (A, B and C). NT=not tested.

TABLE 2

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Presence of CD10+ and leukemia clonogenic cells in SCID mice injected with BV173 cells and treated with bcr-abl (b2/a2) and/or c-myc S!ODNs. Leukemic colonies/ % CD10-positive cells 10 5 cells Treatment Groups PBL SPL BMC PBL SPL BMC

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Control A 1.4 6.1 24.9 19 559 2519 B 0 4.9 11.6 7 252 1579 C 0 5.0 7.4 2 258 1166 b2/a2 S + A NT 6.3 38.5 NT 588 3005 c-myc S B 0 6.5 10.4 4 239 1389 C 0 4.2 7.0 0 194 1214 b2/a2 AS A 0 0 0 0 5 4 B 0 0 0 0 5 9 C 0 0 0 0 9 19 c-myc AS A 0 0 0 0 13 20 B 0 0 0 0 8 37 C 0 0 0 0 4 22 b2/a2 AS + A 0 0 0 0 0 0 c-myc AS B 0 0 0 0 0 1 C 0 0 0 0 0 0

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Immunofluorescence assay detected CD10+cells in peripheral blood (only one mouse positive), spleen and bone marrow of control and sense S! ODNs treated mice, but not in the corresponding tissues of the mice treated with antisense ODNs (Table 2). The more sensitive clonogenic assay revealed several leukemic colonies in peripheral blood, and abundant colonies in spleen and bone marrow of control and sense S! ODNs treated mice. In contrast, cell suspensions of c-myc or b2/a2 antisense-treated mice contained far fewer malignant clonogenic cells (Table 2). Only one of the mice treated with both b2/a2+c-myc antisense ODNs contained detectable clonogenic leukemic cells.

C. Scoring of Superficial Liver Metastases

Superficial liver metastases were scored in mice treated as described in part A., above. The result are described in Table 3, below. Numbers indicate visible liver metastases. Scoring of superficial liver metastases was consistent with immunofluorescence and clonogenic assays. Numerous metastatic nodules were visible on the surface of livers from control and sense-treated mice, several on the livers of mice treated with single antisense, and none on the organs from mice treated with both antisense S! ODNs .

TABLE 3

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Superficial metastases in the liver of SCID mice injected with BV173 cells and treated with b2/a2, c-myc or b2/a2 + c-myc antisense (AS or sense (S) S!ODNs) Treatment Groups Number of Metastases

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Control 89, 54, 88 b2/a2 + c-myc S 156, 107, 61 b2/a2 AS 12, 10, 8 c-myc AS 15, 15, 4 b2/a2 AS + c-myc AS 0, 0, 0

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D. Detection of bcr-abl Transcripts by Reverse Transcriptase-Polymerase Chain Reaction

Cells were collected separately from various organs of S! ODNs treated SCID mice, 56 days after leukemia implantation. Total RNA was extracted from 10 ⁶ cells (Chromczynski et al., Anal. Biochem. 162, 156 (1987)), and divided into two portions. A 3' primer of ABL exon 2, 3' primer of β-actin, 5' primer of BCR exon 2, 5' primer for β-actin, and ABL and β-actin probes recognizing amplified transcripts were all prepared according to published sequences (Szczylik et al., Science 253, 562 (1991); Skorski et al., J. Clin. Invest. 92, 194 (1993); Caracciolo et al., ibid 85, 55 (1990)). One cell sample was reverse transcribed using 400 U of Moloney murine leukemia virus reverse-transcriptase (Bethesda Research Laboratories, Gaithersburg, MD) and 0.1 μg of 3'-end primer of abl exon 2 for 1 hour at 37° C. The second sample was reverse transcribed using the β-actin 3' primer. Resulting cDNA fragments were amplified with 5U Tag polymerase (Perkin Elmer Cetus, Norwalk, CT) in the presence of 5' primer of either BCR exon 2 or β-actin, generating 257-bp and 209-bp fragments of bcr-abl and β-actin, respectively, during 50 cycles of PCR (Chromczynski et al., Anal. Biochem 162; 156 (1987)). Reaction products were electrophoresed, transferred and hybridized, using the appropriate probes (c-abl or β-actin). Blots were exposed 24 hours (bcr-abl) and 2 hours (β-actin).

The results are shown in FIG. 4, indicating detection of bcr-abl transcripts by RT-PCR in RNA from tissues of S!ODN treated (b2/a2+c-myc sense (S); b2/a2 antisense (AS); c-myc AS; or b2/a2+c-myc (AS) or untreated (control) leukemic SCID mice. The blot is representative of three different experiments using three mice/group (PBL=peripheral blood lymphocyte; SPL=spleen; BMC=bone marrow cell; LIV=liver; LNG =lung; and BRN=brain).

RT-PCR amplification of bcr-abl transcripts in RNA isolated from various tissues of control and sense S! ODNs -treated animals (three mice/group) revealed bcr-abl transcripts in each of these tissues. Bcr-abl transcripts were also detected in all tissues except brain of mice treated with single antisense S! ODNs , but the signal was much weaker than observed with control and sense S! ODNs -treated mouse tissues. Even weaker signals were detected in the RNA isolated from all the organs except brain of mice injected with b2/a2 +c-myc antisense S! ODNs , suggesting that the leukemic cell load in mice treated with S! ODNs in was reduced as compared with that of mice treated with individual ODNs. Equal amounts of β-actin detected in each group of organs indicated the integrity and equal loading of the amplified products.

E. Quantitative RT-PCR Detection of bcr-abl Transcripts

To confirm that the differences in the intensity of the bcr-abl bands corresponding to tissues of single versus combined antisense S! ODNs -treated mice reflected the difference in amounts of bcr-abl transcript in the tissues, quantitative RT-PCR (Qt/RT-PCR) was performed using the same amount of RNA isolated from bone marrow cells of b2/a2 and b2/a2+c-myc antisense S!ODN-treated mice, in the presence of increasing amounts of RNA from K562 cells (b3/a2) as a source of competitive bcr-abl RNA, and using optimal concentrations of primers. Integrity of the isolated RNA was confirmed by RT-PCR which detected similar amounts of β-actin transcript. Accordingly, various amounts (zero, 0.1 ng, 1 ng, 10 ng, 100 ng) of total RNA isolated from K562 (b3/a2 junction) cells were added as a source of competitive bcr-abl-containing RNA to the same amount of total RNA isolated from 10 ⁶ BMC obtained from b2/a2 AS or b2/a2 AS+c-myc AS-treated mice. Southern blot analysis of RT-PCR amplification products was performed.

The results of the assay appear in FIG. 5 (lane 1, no K562 RNA; lane 2, 0.1 ng; lane 3, 1 ng; lane 4, 10 ng; lane 5, 100 ng) The blot of FIG. 5 is representative of two different experiments.

The analysis detected the b2/a2 fragment from BV173 RNA contaminating mouse BMC (FIG. 5, lower band) RNA, and the b3/a2 fragment from the K562 RNA (FIG. 5, upper band) added as competitor.

The analysis revealed competitive blocking of the b2/a2 transcript (from BV173 cells present in the tissue) at lower K562 RNA concentrations when bone marrow cells were isolated from mice injected with both b2/a2 and c-myc antisense S! ODNs as compared to those receiving only one antisense S! ODNs (FIG. 5). This indicates the lower amounts of bcr-abl transcripts in bone marrow cell RNA from the combined versus single antisense ODN-treated mice. These results are consistent with those obtained by nonquantitative RT-PCR, immunofluorescence, and clonogenic assays, and by assessment of liver metastases.

F. Leukemic Cell Assay--20 Weeks Post-Transplantation of Leukemic Cells

Two other b2/a2+c-myc antisense S!ODN-treated mice (mice D and E) were subjected to leukemic cell assay 20 weeks after leukemia implantation. At this point, all mice treated with individual S! ODNs were dead. Leukemic colonies were counted after 9-day culture in methylcellulose. The intensity of the RT-PCR band was evaluated after blotting with a junction-specific γ ³² P!-labelled probe and exposing the filters for different times. The assay results, set forth in Table 4, revealed different degrees of disease process as reflected by the tumor load of the two mice: (-) not detectable after 7-day exposure; (+) visible after 7-day exposure; (++) visible after 24 h exposure; (+++) visible after 1 hour exposure. The abbreviations in Table 4 are the same as in FIG. 4:

TABLE 4

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Leukemia growth in SCID mice 20 weeks after injection of 10 6 BV 173 cells and treatment with b2/a2 + c-myc antisense S!ODNs Mice Leukemic Liver colonies/10 5 cell bcr/abl mRNA levels metas PBL SPL BMC PBL SPL BMC LIV LNG BRN tases

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D 0 2 236 - + ++ + + - 0 E 53 283 2387 + +++ +++ +++ + + 23

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G. Survival of Leukemic Cell-Transplanted Mice

Differences in the survival of control, sense, single antisense and dual antisense S!ODN treated mice are summarized in FIG. 6: b2/a2 S+c-myc S (.box-solid.); b2/a2 AS (.tangle-solidup.), c-myc AS (.quadrature.); or b2/a2 AS c-myc AS (.circle-solid.). Control mice (.largecircle.) received diluent only. All nine control and nine sense S!ODN-treated mice died with diffuse leukemia, as confirmed by necropsy, 7-10 weeks after i.v. injection of 10 ⁶ BV173 leukemia cells (median survival time 7.7±0.8 and 8.3±0.5 weeks, respectively). In contrast, the nine b2/a2 antisense S! ODNs - and nine c-myc antisense S! ODNs -treated mice died after 14-18 and 14-19 weeks, respectively, of leukemia growth (median survival time 14.7±0.8 and 14.8±0.9 weeks, respectively; p<0.001 compared with control groups). Seven of nine mice treated with both antisense S! ODNs survived significantly longer (median survival time 26.0±5.4 weeks; p<0.001 compared to mice treated with either antisense ODNs). Two remaining mice were still alive 41 weeks after injection of leukemic cells, but one of them had minimal residual disease as revealed by RT-PCR detection of bcr-abl transcripts in peripheral blood (not shown).

H. Detection of Intact S!ODN in Mouse Tissues and Leukemic Cells Infiltrating Bone Marrow and Spleen

SCID mice were injected (1 mg/day/12 consecutive days) with b2/a2+c-myc AS S! ODNs . Twenty-four hours after the last injection, DNA obtained from 10 ⁶ cells of various tissues was electrophoresed and intracellular S! ODNs were detected by specific hybridization with complementary oligoprobes. The S!ODN detection results are shown in FIG. 7A. For detection of intact S! ODNs in BV173 cells infiltrating mouse tissues, leukemic SCID mice were injected (1 mg/day/12 consecutive days) with bcr-abl, c-myc, or bcr-abl+c-myc AS S! ODNs . Twenty-four hours after the last injection, CD10+BV173 were isolated by immunosorting from bone marrow and spleen cell suspensions. After DNA isolation, intracellular S! ODNs were detected as described previously (Ratajczak et al., Proc. Natl. Acad. Sci. USA 89, 11823 (1993); Kitajima et al. Science 258, 1792 (1992); Higgins et al., PNAS90, 9901 (1993); Skorski et al., PNAS91, 4504 (1994); Huiya et al., ibid 31, 4499 (1994)). Standard 26-met antisense S! ODNs were run as controls. The results are shown in FIG. 7B.

The leukemia suppressive effects of antisense S! ODNs correlated well with their detection in all organs examined except brain, although blot hybridization of tissue DNA isolated 1 day after the last injection showed highest ODNs concentrations in liver and spleen (FIG. 7A). S! ODNs were still detectable in these organs 7 days after the last injection (not shown). Intact b2/a2 and c-myc, antisense S! ODNs were simultaneously detected in vivo in leukemic cells infiltrating bone marrow and spleen of SCID mice one day after completion of the injection protocol, by immunosorting of CD10+cells and Southern blot hybridization of the isolated DNA with oligomer probes complementary to with c-myc or bcr-abl antisense S! ODNs (FIG. 7B).

EXAMPLE 4

Effect of c-raf and c-myc Antisense Oligonucleotides on BV173 Cells

A. Phosphorothioate Oligodeoxynucleotides

The following phosphorothioate oligodeoxynucleotides ( S! ODNs ) were synthesized on an Applied Biosystems model 390Z automated synthesizer. The sequence of each antisense S!ODN was complementary to the first 26 nucleotides of the mRNA transcript of the indicated oncogene, beginning from the translation initiation codon.

c-myc (AS) TTGGTGAAGC TAACGTTGAG GGGCAT (SEQ ID NO:3)

c-myc (S) ATGCCCCTCA ACGTTAGCTT CACCAA (SEQ ID NO:4)

c-raf (AS) GGTGAGGGAG CGGGAGGCGG TCACAT (SEQ ID NO:5)

c-raf (S) ATGTGACCGC CTCCCGCTCC CTCACC (SEQ ID NO:6)

B. Cell Proliferation Assay

BV173 cells (10 ⁴ /100 μl/well) were placed in 96-well culture plates in RPMI medium supplemented with 10% fetal bovine serum, L-glutamine, and penicillin/streptomycin. Sense or antisense S! ODNs were added at the beginning of culture (20 μg/ml) and again (at 50% of the initial dose) 24 and 48 hours later. Control wells received no oligomer. Sense oligonucleotide-treated cells received equal mixtures of c-raf and c-myc sense oligonucleotides. Cells in 96-well plates were counted in Trypan blue on days oncogenes. +4,+6 and +8. The oligonucleotide dosages and results appear in FIG. 8: (.largecircle.) control; (.quadrature.) c-raf plus c-myc sense; (.circle-solid.) c-raf antisense; (m) c-myc antisense, (.tangle-solidup.) c-tar and c-myc antisense. The results indicate that the c-raf and c-myc antisense oligonucleotides acted synergistically in inhibiting leukemic cell proliferation.

EXAMPLE 5

Effect of ras and c-myc Antisense Oligonucleotides on BV173 Cells

The following phosphorothioate oligodeoxynucleotides ( S! ODNs ) were synthesized:

N-ras (AS) CACCACCAGT TTGTACTCAG TCAT (SEQ ID NO:7)

N-ras (S) ATGACTGAGT ACAAACTGGT GGTG (SEQ ID NO:8)

K-ras (AS) TACCACAAGT TTATATTCAG TCAT (SEQ ID NO:9)

K-ras (S) ATGACTGAAT ATAAACTTGT GGTA (SEQ ID NO:10)

H-ras (AS) CACCACCAGC TTATATTCCG TCAT (SEQ ID NO:11)

H-ras (S) ATGACGGAAT ATAAGCTGGT GGTG (SEQ ID NO:12). The sequence of each antisense S!ODN was complementary to the first 24 nucleotides of the mRNA transcript of the indicated oncogene, beginning from the translation initiation codon. A cell proliferation assay according to the procedure of Example 4 was carried out, using ras and c-myc sense and antisense oligonucleotides. For ras oligonucleotide-treated cells, the cells received an equal mixture of a of the above N- , K-, and H-ras oligonucleotides. The oligonucleotide dosages and results appear in FIG. 9: (.largecircle.) control; (.quadrature.) c-ras plus c-myc sense; (.circle-solid.) c-myc antisense; (.box-solid.) ras antisense, (.tangle-solidup.) ras and c-myc antisense. The results indicate that the c-ras and c-myc antisense oligonucleotides acted synergistically in inhibiting leukemic cell proliferation.

Comparative Example 5

Effect of ras and raf Antisense Oligonucleotides on BV173 Cells

The procedure of Example 5 was repeated except that the c-raf oligonucleotides SEQ ID NO:5 (sense) and SEQ ID NO:6 (antisense) were substituted for the corresponding c-myc oligonucleotides. The results are shown in FIG. 10: (.largecircle.) control; (.quadrature.) c-raf plus ras sense; (.circle-solid.) c-tar antisense; (.box-solid.) ras antisense, (.tangle-solidup.) c-raf and ras antisense. The effect of antisense oligonucleotides to c-raf and ras, which are both cytoplasmic oncogenes, was not synergistic, suggesting that synergism requires antisense to at least one cytoplasmic oncogene and at least one nuclear oncogene.

All references cited with respect to synthetic, preparative and analytical procedures are incorporated herein by reference.

The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof and, accordingly, reference should be made to the appended claims, rather than to the foregoing specification, as indication the scope of the invention.

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SEQUENCE LISTING (1) GENERAL INFORMATION: (iii) NUMBER OF SEQUENCES: 55 (2) INFORMATION FOR SEQ ID NO:1: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 26 Nucleotides (B) TYPE: nucleic acid (C) STRANDEDNESS: single stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1: CGCTGAAGGGCTTCTTCCTTATTGAT26 (2) INFORMATION FOR SEQ ID NO:2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 26 Nucleotides (B) TYPE: nucleic acid (C) STRANDEDNESS: single stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: ATCAATAAGGAAGAAGCCCTTCAGCG26 (2) INFORMATION FOR SEQ ID NO:3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 26 Nucleotides (B) TYPE: nucleic acid (C) STRANDEDNESS: single stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: TTGGTGAAGCTAACGTTGAGGGGCAT26 (2) INFORMATION FOR SEQ ID NO:4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 26 Nucleotides (B) TYPE: nucleic acid (C) STRANDEDNESS: single stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: ATGCCCCTCAACGTTAGCTTCACCAA26 (2) INFORMATION FOR SEQ ID NO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 26 Nucleotides (B) TYPE: nucleic acid (C) STRANDEDNESS: single stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: GGTGAGGGAGCGGGAGGCGGTCACAT26 (2) INFORMATION FOR SEQ ID NO:6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 26 Nucleotides (B) TYPE: nucleic acid (C) STRANDEDNESS: single stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: ATGTGACCGCCTCCCGCTCCCTCACC26 (2) INFORMATION FOR SEQ ID NO:7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 24 Nucleotides (B) TYPE: nucleic acid (C) STRANDEDNESS: single stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: CACCACCAGTTTGTACTCAGTCAT24 (2) INFORMATION FOR SEQ ID NO:8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 24 Nucleotides (B) TYPE: nucleic acid (C) STRANDEDNESS: single stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: ATGACTGAGTACAAACTGGTGGTG24 (2) INFORMATION FOR SEQ ID NO:9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 24 Nucleotides (B) TYPE: nucleic acid (C) STRANDEDNESS: single stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: TACCACAAGTTTATATTCAGTCAT24 (2) INFORMATION FOR SEQ ID NO:10: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 24 Nucleotides (B) TYPE: nucleic acid (C) STRANDEDNESS: single stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10: ATGACTGAATATAAACTTGTGGTA24 (2) INFORMATION FOR SEQ ID NO:11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 24 Nucleotides (B) TYPE: nucleic acid (C) STRANDEDNESS: single stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11: CACCACCAGCTTATATTCCGTCAT24 (2) INFORMATION FOR SEQ ID NO:12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 24 Nucleotides (B) TYPE: nucleic acid (C) STRANDEDNESS: single stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12: ATGACGGAATATAAGCTGGTGGTG24 (2) INFORMATION FOR SEQ ID NO:13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 3622 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13: CCCGGGGAGGGGACCGGGGAACAGAGGGCCGAGAGGCGTGCGGCAGGGGGGAGGGTAGGA 60 GAAAGAAGGGCCCGACTGTAGGAGGGCAGCGGAGCATTACCTCATCCCGTGAGCCTCCGC 120 GGGCCCAGAGAAGAATCTTCTAGGGTGGAGTCTCCATGGTGACGGGCGGGCCCGCCCCCC 180 TGAGAGCGACGCGAGCCAATGGGAAGGCCTTGGGGTGACATCATGGGCTATTTTTAGGGG 240 TTGACTGGTAGCAGATAAGTGTTGAGCTCGGGCTGGATAAGGGCTCAGAGTTGCACTGAG 300 TGTGGCTGAAGCAGCGAGGCGGGAGTGGAGGTGCGCGGAGTCAGGCAGACAGACAGACAC 360 AGCCAGCCAGCCAGGTCGGCAGTATAGTCCGAACTGCAAATCTTATTTTCTTTTCACCTT 420 CTCTCTAACTGCCCAGAGCTAGCGCCTGTGGCTCCCGGGCTGGTGGTTCGGGAGTGTCCA 480 GAGAGCCTTGTCTCCAGCCGGCCCCGGGAGGAGAGCCCTGCTGCCCAGGCGCTGTTGACA 540 GCGGCGGAAAGCAGCGGTACCCCACGCGCCCGCCGGGGGACGTCGGCGAGCGGCTGCAGC 600 AGCAAAGAACTTTCCCGGCGGGGAGGACCGGAGACAAGTGGCAGAGTCCCGGAGCGAACT 660 TTTGCAAGCCTTTCCTGCGTCTTAGGCTTCTCCACGGCGGTAAAGACCAGAAGGCGGCGG 720 AGAGCCACGCAAGAGAAGAAGGACGTGCGCTCAGCTTCGCTCGCACCGGTTGTTGAACTT 780 GGGCGAGCGCGAGCCGCGGCTGCCGGGCGCCCCCTCCCCCTAGCAGCGGAGGAGGGGACA 840 AGTCGTCGGAGTCCGGGCGGCCAAGACCCGCCGCCGGCCGGCCACTGCAGGGTCCGCACT 900 GATCCGCTCCGCGGGGAGAGCCGCTGCTCTGGGAAGTGAGTTCGCCTGCGGACTCCGAGG 960 AACCGCTGCGCCCGAAGAGCGCTCAGTGAGTGACCGCGACTTTTCAAAGCCGGGTAGCGC 1020 GCGCGAGTCGACAAGTAAGAGTGCGGGAGGCATCTTAATTAACCCTGCGCTCCCTGGAGC 1080 GAGCTGGTGAGGAGGGCGCAGCGGGGACGACAGCCAGCGGGTGCGTGCGCTCTTAGAGAA 1140 ACTTTCCCTGTCAAAGGCTCCGGGGGGCGCGGGTGTCCCCCGCTTGCCAGAGCCCTGTTG 1200 CGGCCCCGAAACTTGTGCGCGCACGCCAAACTAACCTCACGTGAAGTGACGGACTGTTCT 1260 ATGACTGCAAAGATGGAAACGACCTTCTATGACGATGCCCTCAACGCCTCGTTCCTCCCG 1320 TCCGAGAGCGGACCTTATGGCTACAGTAACCCCAAGATCCTGAAACAGAGCATGACCCTG 1380 AACCTGGCCGACCCAGTGGGGAGCCTGAAGCCGCACCTCCGCGCCAAGAACTCGGACCTC 1440 CTCACCTCGCCCGACGTGGGGCTGCTCAAGCTGGCGTCGCCCGAGCTGGAGCGCCTGATA 1500 ATCCAGTCCAGCAACGGGCACATCACCACCACGCCGACCCCCACCCAGTTCCTGTGCCCC 1560 AAGAACGTGACAGATGAGCAGGAGGGGTTCGCCGAGGGCTTCGTGCGCGCCCTGGCCGAA 1620 CTGCACAGCCAGAACACGCTGCCCAGCGTCACGTCGGCGGCGCAGCCGGTCAACGGGGCA 1680 GGCATGGTGGCTCCCGCGGTAGCCTCGGTGGCAGGGGGCAGCGGCAGCGGCGGCTTCAGC 1740 GCCAGCCTGCACAGCGAGCCGCCGGTCTACGCAAACCTCAGCAACTTCAACCCAGGCGCG 1800 CTGAGCAGCGGCGGCGGGGCGCCCTCCTACGGCGCGGCCGGCCTGGCCTTTCCCGCGCAA 1860 CCCCAGCAGCAGCAGCAGCCGCCGCACCACCTGCCCCAGCAGATGCCCGTGCAGCACCCG 1920 CGGCTGCAGGCCCTGAAGGAGGAGCCTCAGACAGTGCCCGAGATGCCCGGCGAGACACCG 1980 CCCCTGTCCCCCATCGACATGGAGTCCCAGGAGCGGATCAAGGCGGAGAGGAAGCGCATG 2040 AGGAACCGCATCGCTGCCTCCAAGTGCCGAAAAAGGAAGCTGGAGAGAATCGCCCGGCTG 2100 GAGGAAAAAGTGAAAACCTTGAAAGCTCAGAACTCGGAGCTGGCGTCCACGGCCAACATG 2160 CTCAGGGAACAGGTGGCACAGCTTAAACAGAAAGTCATGAACCACGTTAACAGTGGGTGC 2220 CAACTCATGCTAACGCAGCAGTTGCAAACATTTTGAAGAGAGACCGTCGGGGGCTGAGGG 2280 GCAACGAAGAAAAAAAATAACACAGAGAGACAGACTTGAGAACTTGACAAGTTGCGACGG 2340 AGAGAAAAAAGAAGTGTCCGAGAACTAAAGCCAAGGGTATCCAAGTTGGACTGGGTTCGG 2400 TCTGACGGCGCCCCCAGTGTGCACGAGTGGGAAGGACTTGGTCGCGCCCTCCCTTGGCGT 2460 GGAGCCAGGGAGCGGCCGCCTGCGGGCTGCCCCGCTTTGCGGACGGGCTGTCCCCGCGCG 2520 AACGGAACGTTGGACTTTCGTTAACATTGACCAAGAACTGCATGGACCTAACATTCGATC 2580 TCATTCAGTATTAAAGGGGGGAGGGGGAGGGGGTTACAAACTGCAATAGAGACTGTAGAT 2640 TGCTTCTGTAGTACTCCTTAAGAACACAAAGCGGGGGGAGGGTTGGGGAGGGGCGGCAGG 2700 AGGGAGGTTTGTGAGAGCGAGGCTGAGCCTACAGATGAACTCTTTCTGGCCTGCTTTCGT 2760 TAACTGTGTATGTACATATATATATTTTTTAATTTGATTAAAGCTGATTACTGTCAATAA 2820 ACAGCTTCATGCCTTTGTAAGTTATTTCTTGTTTGTTTGTTTGGGTATCCTGCCCAGTGT 2880 TGTTTGTAAATAAGAGATTTGGAGCACTCTGAGTTTACCATTTGTAATAAAGTATATAAT 2940 TTTTTTATGTTTTGTTTCTGAAAATTCCAGAAAGGATATTTAAGAAAATACAATAAACTA 3000 TTGGAAAGTACTCCCCTAACCTCTTTTCTGCATCATCTGTAGATCCTAGTCTATCTAGGT 3060 GGAGTTGAAAGAGTTAAGAATGCTCGATAAAATCACTCTCAGTGCTTCTTACTATTAAGC 3120 AGTAAAAACTGTTCTCTATTAGACTTAGAAATAAATGTACCTGATGTACCTGATGCTATG 3180 TCAGGCTTCATACTCCACGCTCCCCCAGCGTATCTATATGGAATTGCTTACCAAAGGCTA 3240 GTGCGATGTTTCAGGAGGCTGGAGGAAGGGGGGTTGCAGTGGAGAGGGACAGCCCACTGA 3300 GAAGTCAAACATTTCAAAGTTTGGATTGCATCAAGTGGCATGTGCTGTGACCATTTATAA 3360 TGTTAGAAATTTTACAATAGGTGCTTATTCTCAAAGCAGGAATTGGTGGCAGATTTTACA 3420 AAAGATGTATCCTTCCAATTTGGAATCTTCTCTTTGACAATTCCTAGATAAAAAGATGGC 3480 CTTTGTCTTATGAATATTTATAACAGCATTCTGTCACAATAAATGTATTCAAATACCAAT 3540 AACAGATCTTGAATTGCTTCCCTTTACTACTTTTTTGTTCCCAAGTTATATACTGAAGTT 3600 TTTATTTTTAGTTGCTGAGGTT3622 (2) INFORMATION FOR SEQ ID NO:14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6453 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14: GGATCCCAGCCTTTCCCCAGCCCGTAGCCCCGGGACCTCCGCGGTGGGCGGCGCCGCGCT 60 GCCGGCGCAGGGAGGGCCTCTGGTGCACCGGCACCGCTGAGTCGGGTTCTCTCGCCGGCC 120 TGTTCCCGGGAGAGCCCGGGGCCCTGCTCGGAGATGCCGCCCCGGGCCCCCAGACACCGG 180 CTCCCTGGCCTTCCTCGAGCAACCCCGAGCTCGGCTCCGGTCTCCAGCCAAGCCCAACCC 240 CGAGAGGCCGCGGCCCTACTGGCTCCGCCTCCCGCGTTGCTCCCGGAAGCCCCGCCCGAC 300 CGCGGCTCCTGACAGACGGGCCGCTCAGCCAACCGGGGTGGGGCGGGGCCCGATGGCGCG 360 CAGCCAATGGTAGGCCGCGCCTGGCAGACGGACGGGCGCGGGGCGGGGCGTGCGCAGGCC 420 CGCCCGAGTCTCCGCCGCCCGTGCCCTGCGCCCGCAACCCGAGCCGCACCCGCCGCGGAC 480 GGAGCCCATGCGCGGGGCGAACCGCGCGCCCCCGCCCCCGCCCCGCCCCGGCCTCGGCCC 540 CGGCCCTGGCCCCGGGGGCAGTCGCGCCTGTGAACGGTGAGTGCGGGCAGGGATCGGCCG 600 GGCCGCGCGCCCTCCTCGCCCCCAGGCGGCAGCAATACGCGCGGCGCGGGCCGGGGGCGC 660 GGGGCCGGCGGGCGTAAGCGGCGGCGGCGGCGGCGGGTGGGTGGGGCCGGGCGGGGCCCG 720 CGGGCACAGGTGAGCGGGCGTCGGGGGCTGCGGCGGGCGGGGGCCCCTTCCTCCCTGGGG 780 CCTGCGGGAATCCGGGCCCCACCCGTGGCCTCGCGCTGGGCACGGTCCCCACGCCGGCGT 840 ACCCGGGAGCCTCGGGCCCGGCGCCCTCACACCCGGGGGCGTCTGGGAGGAGGCGGCCGC 900 GGCCACGGCACGCCCGGGCACCCCCGATTCAGCATCACAGGTCGCGGACCAGGCCGGGGG 960 CCTCAGCCCCAGTGCCTTTTCCCTCTCCGGGTCTCCCGCGCCGCTTCTCGGCCCCTTCCT 1020 GTCGCTCAGTCCCTGCTTCCCAGGAGCTCCTCTGTCTTCTCCAGCTTTCTGTGGCTGAAA 1080 GATGCCCCCGGTTCCCCGCCGGGGGTGCGGGGCGCTGCCCGGGTCTGCCCTCCCCTCGGC 1140 GGCGCCTAGTACGCAGTAGGCGCTCAGCAAATACTTGTCGGAGGCACCAGCGCCGCGGGG 1200 CCTGCAGGCTGGCACTAGCCTGCCCGGGCACGCCGTGGCGCGCTCCGCCGTGGCCAGACC 1260 TGTTCTGGAGGACGGTAACCTCAGCCCTCGGGCGCCTCCCTTTAGCCTTTCTGCCGACCC 1320 AGCAGCTTCTAATTTGGGTGCGTGGTTGAGAGCGCTCAGCTGTCAGCCCTGCCTTTGAGG 1380 GCTGGGTCCCTTTTCCCATCACTGGGTCATTAAGAGCAAGTGGGGGCGAGGCGACAGCCC 1440 TCCCGCACGCTGGGTTGCAGCTGCACAGGTAGGCACGCTGCAGTCCTTGCTGCCTGGCGT 1500 TGGGGCCCAGGGACCGCTGTGGGTTTGCCCTTCAGATGGCCCTGCCAGCAGCTGCCCTGT 1560 GGGGCCTGGGGCTGGGCCTGGGCCTGGCTGAGCAGGGCCCTCCTTGGCAGGTGGGGCAGG 1620 AGACCCTGTAGGAGGACCCCGGGCCGCAGGCCCCTGAGGAGCGATGACGGAATATAAGCT 1680 GGTGGTGGTGGGCGCCGGCGGTGTGGGCAAGAGTGCGCTGACCATCCAGCTGATCCAGAA 1740 CCATTTTGTGGACGAATACGACCCCACTATAGAGGTGAGCCTAGCGCCGCCGTCCAGGTG 1800 CCAGCAGCTGCTGCGGGCGAGCCCAGGACACAGCCAGGATAGGGCTGGCTGCAGCCCCTG 1860 GTCCCCTGCATGGTGCTGTGGCCCTGTCTCCTGCTTCCTCTAGAGGAGGGGAGTCCCTCG 1920 TCTCAGCACCCCAGGAGAGGAGGGGGCATGAGGGGCATGAGAGGTACCAGGGAGAGGCTG 1980 GCTGTGTGAACTCCCCCCACGGAAGGTCCTGAGGGGGTCCCTGAGCCCTGTCCTCCTGCA 2040 GGATTCCTACCGGAAGCAGGTGGTCATTGATGGGGAGACGTGCCTGTTGGACATCCTGGA 2100 TACCGCCGGCCAGGAGGAGTACAGCGCCATGCGGGACCAGTACATGCGCACCGGGGAGGG 2160 CTTCCTGTGTGTGTTTGCCATCAACAACACCAAGTCTTTTGAGGACATCCACCAGTACAG 2220 GTGAACCCCGTGAGGCTGGCCCGGGAGCCCACGCCGCACAGGTGGGGCCAGGCCGGCTGC 2280 GTCCAGGCAGGGGCCTCCTGTCCTCTCTGCGCATGTCCTGGATGCCGCTGCGCCTGCAGC 2340 CCCCGTAGCCAGCTCTCGCTTTCCACCTCTCAGGGAGCAGATCAAACGGGTGAAGGACTC 2400 GGATGACGTGCCCATGGTGCTGGTGGGGAACAAGTGTGACCTGGCTGCACGCACTGTGGA 2460 ATCTCGGCAGGCTCAGGACCTCGCCCGAAGCTACGGCATCCCCTACATCGAGACCTCGGC 2520 CAAGACCCGGCAGGTGAGGCAGCTCTCCACCCCACAGCTAGCCAGGGACCCGCCCCGCCC 2580 CGCCCCAGCCAGGGAGCAGCACTCACTGACCCTCTCCCTTGACACAGGGCAGCCGCTCTG 2640 GCTCTAGCTCCAGCTCCGGGACCCTCTGGGACCCCCCGGGACCCATGTGACCCAGCGGCC 2700 CCTCGCACTGTAGGTCTCCCGGGACGGCAGGGCAGTGAGGGAGGCGAGGGCCGGGGTCTG 2760 GGCTCACGCCCTGCAGTCCTGGGCCGACACAGCTCCGGGGAAGGCGGAGGTCCTTGGGGA 2820 GAGCTGCCCTGAGCCAGGCCGGAGCGGTGACCCTGGGGCCCGGCCCCTCTTGTCCCCAGA 2880 GTGTCCCACGGGCACCTGTTGGTTCTGAGTCTTAGTGGGGCTACTGGGGACACGGGCCGT 2940 AGCTGAGTCGAGAGCTGGGTGCAGGGTGGTCAAACCCTGGCCAGACCTGGAGTTCAGGAG 3000 GGCCCCGGGCCACCCTGACCTTTGAGGGGCTGCTGTAGCATGATGCGGGTGGCCCTGGGC 3060 ACTTCGAGATGGCCAGAGTCCAGCTTCCCGTGTGTGTGGTGGGCCTGGGGAAGTGGCTGG 3120 TGGAGTCGGGAGCTTCGGGCCAGGCAAGGCTTGATCCCACAGCAGGGAGCCCCTCACCCA 3180 GGCAGGCGGCCACAGGCCGGTCCCTCCTGATCCCATCCCTCCTTTCCCAGGGAGTGGAGG 3240 ATGCCTTCTACACGTTGGTGCGTGAGATCCGGCAGCACAAGCTGCGGAAGCTGAACCCTC 3300 CTGATGAGAGTGGCCCCGGCTGCATGAGCTGCAAGTGTGTGCTCTCCTGACGCAGGTGAG 3360 GGGGACTCCCAGGGCGGCCGCCACGCCCACCGGATGACCCCGGCTCCCCGCCCCTGCCGG 3420 TCTCCTGGCCTGCGGTCAGCAGCCTCCCTTGTGCCCCGCCCAGCACAAGCTCAGGACATG 3480 GAGGTGCCGGATGCAGGAAGGAGGTGCAGACGGAAGGAGGAGGAAGGAAGGACGGAAGCA 3540 AGGAAGGAAGGAAGGGCTGCTGGAGCCCAGTCACCCCGGGACCGTGGGCCGAGGTGACTG 3600 CAGACCCTCCCAGGGAGGCTGTGCACAGACTGTCTTGAACATCCCAAATGCCACCGGAAC 3660 CCCAGCCCTTAGCTCCCCTCCCAGGCCTCTGTGGGCCCTTGTCGGGCACAGATGGGATCA 3720 CAGTAAATTATTGGATGGTCTTGATCTTGGTTTTCGGCTGAGGGTGGGACACGGTGCGCG 3780 TGTGGCCTGGCATGAGGTATGTCGGAACCTCAGGCCTGTCCAGCCCTGGGCTCTCCATAG 3840 CCTTTGGGAGGGGGAGGTTGGGAGAGGCCGGTCAGGGGTCTGGGCTGTGGTGCTCTCTCC 3900 TCCCGCCTGCCCCAGTGTCCACGGCTTCTGGCAGAGAGCTCTGGACAAGCAGGCAGATCA 3960 TAAGGACAGAGAGCTTACTGTGCTTCTACCAACTAGGAGGGCGTCCTGGTCCTCCAGAGG 4020 GAGGTGGTTTCAGGGGTTGGGGATCTGTGCCGGTGGCTCTGGTCTCTGCTGGGAGCCTTC 4080 TTGGCGGTGAGAGGCATCACCTTTCCTGACTTGCTCCCAGCGTGAAATGCACCTGCCAAG 4140 AATGGCAGACATAGGGACCCCGCCTCCTGGGCCTTCACATGCCCAGTTTTCTTCGGCTCT 4200 GTGGCCTGAAGCGGTCTGTGGACCTTGGAAGTAGGGCTCCAGCACCGACTGGCCTCAGGC 4260 CTCTGCCTCATTGGTGGTCGGGTAGCGGCCAGTAGGGCGTGGGAGCCTGGCCATCCCTGC 4320 CTCCTGGAGTGGACGAGGTTGGCAGCTGGTCCGTCTGCTCCTGCCCCACTCTCCCCCGCC 4380 CCTGCCCTCACCCTACCCTTGCCCCACGCCTGCCTCATGGCTGGTTGCTCTTGGAGCCTG 4440 GTAGTGTCACTGGCTCAGCCTTGCTGGGTATACACAGGCTCTGCCACCCACTCTGCTCCA 4500 AGGGGCTTGCCCTGCCTTGGGCCAAGTTCTAGGTCTGGCCACAGCCACAGACAGCTCAGT 4560 CCCCTGTGTGGTCATCCTGGCTTCTGCTGGGGGCCCACAGCGCCCCTGGTGCCCCTCCCC 4620 TCCCAGGGCCCGGGTTGAGGCTGGGCCAGGCCCTCTGGGACGGGGACTTGTGCCCTGTCA 4680 GGGTTCCCTATCCCTGAGGTTGGGGGAGAGCTAGCAGGGCATGCCGCTGGCTGGCCAGGG 4740 CTGCAGGGACACTCCCCCTTTTGTCCAGGGAATACCACACTCGCCCTTCTCTCCAGCGAA 4800 CACCACACTCGCCCTTCTCTCCAGGGGACGCCACACTCCCCCTTCTGTCCAGGGGACGCC 4860 ACACTCCCCCTTCTCTCCAGGGGACGCCACACTCGCCCTTCTCTCCAGGGGACGCCACAC 4920 TCGCCCTTCTCTCCAGGGGACGCCACACTCGCCCTTCTGTCCAGGGGACGCCACACTCGC 4980 CCTTCTCTCCAGGGGACGCCACACTCGCCCTTCTCTCCAGGGGACGCCACACTCCCCCTT 5040 CTGTCCAGGGGACGCCACACTCCCCCTTCTCTCCAGGGGACGCCACACTCCCCCTTCTCT 5100 CCAGGGGACGCCACACTCGCCCTTCTCTCCAGGGGACGCCACACTCCCCCTTCTGTCCAG 5160 GGGACGCCACACTCGCCCTTCTCTCCAGGGGACGCCACACTCGCCCTTCTCTCCAGGGGA 5220 CGCCACACTCCCCCTTCTCTCCAGGGGACGCCACACTCCCCCTTCTCTCCAGGGGACGCC 5280 ACACTCCCCCTTCTGTCCAGGGGACGCCACACTCGCCCTTCTCTCCAGGGGACGCCACAC 5340 TCCCCCTTCTCTCCAGGGGACGCCACACTCCCCCTTCTCTCCAGGGGACGCCACACTCCC 5400 CCTTCTGTCCAGGGGACGCCACACTCGCCCTTCTCTCCAGGGGACGCCACACTCGCCCTT 5460 CTCTCCAGGGGACGCCACACTCGCCCTTCTCTCCAGGGGACGCCACACTTGCCCTTCTGT 5520 CCAGGGAATGCCACACTCCCCCTTCTCCCCAGCAGCCTCCGAGTGACCAGCTTCCCCATC 5580 GATAGACTTCCCGAGGCCAGGAGCCCTCTAGGGCTGCCGGGTGCCACCCTGGCTCCTTCC 5640 ACACCGTGCTGGTCACTGCCTGCTGGGGGCGTCAGATGCAGGTGACCCTGTGCAGGAGGT 5700 ATCTCTGGACCTGCCTCTTGGTCATTACGGGGCTGGGCAGGGCCTGGTATCAGGGCCCCG 5760 CTGGGGTTGCAGGGCTGGGCCTGTGCTGTGGTCCTGGGGTGTCCAGGACAGACGTGGAGG 5820 GGTCAGGGCCCAGCACCCCTGCTCCATGCTGAACTGTGGGAAGCATCCAGGTCCCTGGGT 5880 GGCTTCAACAGGAGTTCCAGCACGGGAACCACTGGACAACCTGGGGTGTGTCCTGATCTG 5940 GGGACAGGCCAGCCACACCCCGAGTCCTAGGGACTCCAGAGAGCAGCCCACTGCCCTGGG 6000 CTCCACGGAAGCCCCCTCATGCCGCTAGGCCTTGGCCTCGGGGACAGCCCAGCTAGGCCA 6060 GTGTGTGGCAGGACCAGGCCCCCATGTGGGAGCTGACCCCTTGGGATTCTGGAGCTGTGC 6120 TGATGGGCAGGGGAGAGCCAGCTCCTCCCCTTGAGGGAGGGTCTTGATGCCTGGGGTTAC 6180 CCGCAGAGGCCTGGGTGCCGGGACGCTCCCCGGTTTGGCTGAAAGGAAAGCAGATGTGGT 6240 CAGCTTCTCCACTGAGCCCATCTGGTCTTCCCGGGGCTGGGCCCCATAGATCTGGGTCCC 6300 TGTGTGGCCCCCCTGGTCTGATGCCGAGGATACCCCTGCAAACTGCCAATCCCAGAGGAC 6360 AAGACTGGGAAGTCCCTGCAGGGAGAGCCCATCCCCGCACCCTGACCCACAAGAGGGACT 6420 CCTGCTGCCCACCAGGCATCCCTCCAGGGATCC6453 (2) INFORMATION FOR SEQ ID NO:15: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5775 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15: TCCTAGGCGGCGGCCGCGGCGGCGGAGGCAGCAGCGGCGGCGGCAGTGGCGGCGGCGAAG 60 GTGGCGGCGGCTCGGCCAGTACTCCCGGCCCCCGCCATTTCGGACTGGGAGCGAGCGCGG 120 CGCAGGCACTGAAGGCGGCGGCGGGGCCAGAGGCTCAGCGGCTCCCAGGTGCGGGAGAGA 180 GGCCTGCTGAAAATGACTGAATATAAACTTGTGGTAGTTGGAGCTTGTGGCGTAGGCAAG 240 AGTGCCTTGACGATACAGCTAATTCAGAATCATTTTGTGGACGAATATGATCCAACAATA 300 GAGGATTCCTACAGGAAGCAAGTAGTAATTGATGGAGAAACCTGTCTCTTGGATATTCTC 360 GACACAGCAGGTCAAGAGGAGTACAGTGCAATGAGGGACCAGTACATGAGGACTGGGGAG 420 GGCTTTCTTTGTGTATTTGCCATAAATAATACTAAATCATTTGAAGATATTCACCATTAT 480 AGAGAACAAATTAAAAGAGTTAAGGACTCTGAAGATGTACCTATGGTCCTAGTAGGAAAT 540 AAATGTGATTTGCCTTCTAGAACAGTAGACACAAAACAGGCTCAGGACTTAGCAAGAAGT 600 TATGGAATTCCTTTTATTGAAACATCAGCAAAGACAAGACAGGGTGTTGATGATGCCTTC 660 TATACATTAGTTCGAGAAATTCGAAAACATAAAGAAAAGATGAGCAAAGATGGTAAAAAG 720 AAGAAAAAGAAGTCAAAGACAAAGTGTGTAATTATGTAAATACAATTTGTACTTTTTTCT 780 TAAGGCATACTAGTACAAGTGGTAATTTTTGTACATTACACTAAATTATTAGCATTTGTT 840 TTAGCATTACCTAATTTTTTTCCTGCTCCATGCAGACTGTTAGCTTTTACCTTAAATGCT 900 TATTTTAAAATGACAGTGGAAGTTTTTTTTTCCTCGAAGTGCCAGTATTCCCAGAGTTTT 960 GGTTTTTGAACTAGCAATGCCTGTGAAAAAGAAACTGAATACCTAAGATTTCTGTCTTGG 1020 GGTTTTTGGTGCATGCAGTTGATTACTTCTTATTTTTCTTACCAAGTGTGAATGTTGGTG 1080 TGAAACAAATTAATGAAGCTTTTGAATCATCCCTATTCTGTGTTTTATCTAGTCACATAA 1140 ATGGATTAATTACTAATTTCAGTTGAGACCTTCTAATTGGTTTTTACTGAAACATTGAGG 1200 GACACAAATTTATGGGCTTCCTGATGATGATTCTTCTAGGCATCATGTCCTATAGTTTGT 1260 CATCCCTGATGAATGTAAAGTTACACTGTTCACAAAGGTTTTGTCTCCTTTCCACTGCTA 1320 TTAGTCATGGTCACTCTCCCCAAAATATTATATTTTTTCTATAAAAAGAAAAAAATGGAA 1380 AAAAATTACAAGGCAATGGAAACTATTATAAGGCCATTTCCTTTTCACATTAGATAAATT 1440 ACTATAAAGACTCCTAATAGCTTTTTCCTGTTAAGGCAGACCCAGTATGAATGGGATTAT 1500 TATAGCAACCATTTTGGGGCTATATTTACATGCTACTAAATTTTTATAATAATTGAAAAG 1560 ATTTTAACAAGTATAAAAAAATTCTCATAGGAATTAAATGTAGTCTCCCTGTGTCAGACT 1620 GCTCTTTCATAGTATAACTTTAAATCTTTTCTTCAACTTGAGTCTTTGAAGATAGTTTTA 1680 ATTCTGCTTGTGACATTAAAAGATTATTTGGGCCAGTTATAGCTTATTAGGTGTTGAAGA 1740 GACCAAGGTTGCAAGCCAGGCCCTGTGTGAACCTTGAGCTTTCATAGAGAGTTTCACAGC 1800 ATGGACTGTGTGCCCCACGGTCATCCGAGTGGTTGTACGATGCATTGGTTAGTCAAAAAT 1860 GGGGAGGGACTAGGGCAGTTTGGATAGCTCAACAAGATACAATCTCACTCTGTGGTGGTC 1920 CTGCTGACAAATCAAGAGCATTGCTTTTGTTTCTTAAGAAAACAAACTCTTTTTTAAAAA 1980 TTACTTTTAAATATTAACTCAAAAGTTGAGATTTTGGGGTGGTGGTGTGCCAAGACATTA 2040 ATTTTTTTTTTAAACAATGAAGTGAAAAAGTTTTACAATCTCTAGGTTTGGCTAGTTCTC 2100 TTAACACTGGTTAAATTAACATTGCATAAACACTTTTCAAGTCTGATCCATATTTAATAA 2160 TGCTTTAAAATAAAAATAAAAACAATCCTTTTGATAAATTTAAAATGTTACTTATTTTAA 2220 AATAAATGAAGTGAGATGGCATGGTGAGGTGAAAGTATCACTGGACTAGGTTGTTGGTGA 2280 CTTAGGTTCTAGATAGGTGTCTTTTAGGACTCTGATTTTGAGGACATCACTTACTATCCA 2340 TTTCTTCATGTTAAAAGAAGTCATCTCAAACTCTTAGTTTTTTTTTTTTACACTATGTGA 2400 TTTATATTCCATTTACATAAGGATACACTTATTTGTCAAGCTCAGCACAATCTGTAAATT 2460 TTTAACCTATGTTACACCATCTTCAGTGCCAGTCTTGGGCAAAATTGTGCAAGAGGTGAA 2520 GTTTATATTTGAATATCCATTCTCGTTTTAGGACTCTTCTTCCATATTAGTGTCATCTTG 2580 CCTCCCTACCTTCCACATGCCCCATGACTTGATGCAGTTTTAATACTTGTAATTCCCCTA 2640 ACCATAAGATTTACTGCTGCTGTGGATATCTCCATGAAGTTTTCCCACTGAGTCACATCA 2700 GAAATGCCCTACATCTTATTTTCCTCAGGGCTCAAGAGAATCTGACAGATACCATAAAGG 2760 GATTTGACCTAATCACTAATTTTCAGGTGGTGGCTGATGCTTTGAACATCTCTTTGCTGC 2820 CCAATCCATTAGCGACAGTAGGATTTTTCAACCCTGGTATGAATAGACAGAACCCTATCC 2880 AGTGGAAGGAGAATTTAATAAAGATAGTGCAGAAAGAATTCCTTAGGTAATCTATAACTA 2940 GGACTACTCCTGGTAACAGTAATACATTCCATTGTTTTAGTAACCAGAAATCTTCATGCA 3000 ATGAAAAATACTTTAATTCATGAAGCTTACTTTTTTTTTTTTGGTGTCAGAGTCTCGCTC 3060 TTGTCACCCAGGCTGGAATGCAGTGGCGCCATCTCAGCTCACTGCAACCTTCCATCTTCC 3120 CAGGTTCAAGCGATTCTCGTGCCTCGGCCTCCTGAGTAGCTGGGATTACAGGCGTGTGCA 3180 CTACACTCAACTAATTTTTGTATTTTTAGGAGAGACGGGGTTTCACCTGTTGGCCAGGCT 3240 GGTCTCGAACTCCTGACCTCAAGTGATTCACCCACCTTGGCCTCATAAACCTGTTTTGCA 3300 GAACTCATTTATTCAGCAAATATTTATTGAGTGCCTACCAGATGCCAGTCACCGCACAAG 3360 GCACTGGGTATATGGTATCCCCAAACAAGAGACATAATCCCGGTCCTTAGGTACTGCTAG 3420 TGTGGTCTGTAATATCTTACTAAGGCCTTTGGTATACGACCCAGAGATAACACGATGCGT 3480 ATTTTAGTTTTGCAAAGAAGGGGTTTGGTCTCTGTGCCAGCTCTATAATTGTTTTGCTAC 3540 GATTCCACTGAAACTCTTCGATCAAGCTACTTTATGTAAATCACTTCATTGTTTTAAAGG 3600 AATAAACTTGATTATATTGTTTTTTTATTTGGCATAACTGTGATTCTTTTAGGACAATTA 3660 CTGTACACATTAAGGTGTATGTCAGATATTCATATTGACCCAAATGTGTAATATTCCAGT 3720 TTTCTCTGCATAAGTAATTAAAATATACTTAAAAATTAATAGTTTTATCTGGGTACAAAT 3780 AAACAGTGCCTGAACTAGTTCACAGACAAGGGAAACTTCTATGTAAAAATCACTATGATT 3840 TCTGAATTGCTATGTGAAACTACAGATCTTTGGAACACTGTTTAGGTAGGGTGTTAAGAC 3900 TTGACACAGTACCTCGTTTCTACACAGAGAAAGAAATGGCCATACTTCAGGAACTGCAGT 3960 GCTTATGAGGGGATATTTAGGCCTCTTGAATTTTTGATGTAGATGGGCATTTTTTTAAGG 4020 TAGTGGTTAATTACCTTTATGTGAACTTTGAATGGTTTAACAAAAGATTTGTTTTTGTAG 4080 AGATTTTAAAGGGGGAGAATTCTAGAAATAAATGTTACCTAATTATTACAGCCTTAAAGA 4140 CAAAAATCCTTGTTGAAGTTTTTTTAAAAAAAGACTAAATTACATAGACTTAGGCATTAA 4200 CATGTTTGTGGAAGAATATAGCAGACGTATATTGTATCATTTGAGTGAATGTTCCCAAGT 4260 AGGCATTCTAGGCTCTATTTAACTGAGTCACACTGCATAGGAATTTAGAACCTAACTTTT 4320 ATAGGTTATCAAAACTGTTGTCACCATTGCACAATTTTGTCCTAATATATACATAGAAAC 4380 TTTGTGGGGCATGTTAAGTTACAGTTTGCACAAGTTCATCTCATTTGTATTCCATTGATT 4440 TTTTTTTTTCTTCTAAACATTTTTTCTTCAAAACAGTATATATAACTTTTTTTAGGGGAT 4500 TTTTTTTAGACAGCAAAAAACTATCTGAAGATTTCCATTTGTCAAAAAGTAATGATTTCT 4560 TGATAATTGTGTAGTGAATGTTTTTTAGAACCCAGCAGTTACCTTGAAAGCTGAATTTAT 4620 ATTTAGTAACTTCTGTGTTAATACTGGATAGCATGAATTCTGCATTGAGAAACTGAATAG 4680 CTGTCATAAAATGCTTTCTTTCCTAAAGAAAGATACTCACATGAGTTCTTGAAGAATAGT 4740 CATAACTAGATTAAGATCTGTGTTTTAGTTTAATAGTTTGAAGTGCCTGTTTGGGATAAT 4800 GATAGGTAATTTAGATGAATTTAGGGGAAAAAAAAGTTATCTGCAGTTATGTTGAGGGCC 4860 CATCTCTCCCCCCACACCCCCACAGAGCTAACTGGGTTACAGTGTTTTATCCGAAAGTTT 4920 CCAATTCCACTGTCTTGTGTTTTCATGTTGAAAATACTTTTGCATTTTTCCTTTGAGTGC 4980 CAATTTCTTACTAGTACTATTTCTTAATGTAACATGTTTACCTGGCCTGTCTTTTAACTA 5040 TTTTTGTATAGTGTAAACTGAAACATGCACATTTTGTACATTGTGCTTTCTTTTGTGGGT 5100 CATATGCAGTGTGATCCAGTTGTTTTCCATCATTTGGTTGCGCTGACCTAGGAATGTTGG 5160 TCATATCAAACATTAAAAATGACCACTCTTTTAATGAAATTAACTTTTAAATGTTTATAG 5220 GAGTATGTGCTGTGAAGTGATCTAAAATTTGTAATATTTTTGTCATGAACTGTACTACTC 5280 CTAATTATTGTAATGTAATAAAAATAGTTACAGTGACTATGAGTGTGTATTTATTCATGC 5340 AAATTTGAACTGTTTGCCCCGAAATGGATATGGATACTTTATAAGCCATAGACACTATAG 5400 TATACCAGTGAATCTTTTATGCAGCTTGTTAGAAGTATCCTTTTATTTTCTAAAAGGTGC 5460 TGTGGATATTATGTAAAGGCGTGTTTGCTTAAACAATTTTCCATATTTAGAAGTAGATGC 5520 AAAACAAATCTGCCTTTATGACAAAAAAATAGGATAACATTATTTATTTATTTCCTTTTA 5580 TCAATAAGGTAATTGATACACAACAGGTGACTTGGTTTTAGGCCCAAAGGTAGCAGCAGC 5640 AACATTAATAATGGAAATAATTGAATAGTTAGTTATGTATGTTAATGCCAGTCACCAGCA 5700 GGCTATTTCAAGGTCAGAAGTAATGACTCCATACATATTATTTATTTCTATAACTACATT 5760 TAAATCATTACCAGG5775 (2) INFORMATION FOR SEQ ID NO:16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2436 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16: CTGCAGCTTCTAGGACCCGGTTTCTTTTACTGATTTAAAAACAAAACAAAAAAAAATAAA 60 AAAGTTGTGCCTGAAATGAATCTTGTTTTTTTTTTATAAGTAGCCGCCTGGTTACTGTGT 120 CCTGTAAAATACAGACATTGACCCTTGGTGTAGCTTCTGTTCAACTTTATATCACGGGAA 180 TGGATGGGTCTGATTTCTTGGCCCTCTTCTTGAATTGGCCATATACAGGGTCCCTGGCCA 240 GTGGACTGAAGGCTTTGTCTAAGATGACAAGGGTCAGCTCAGGGGATGTGGGGGAGGGCG 300 GTTTTATCTTCCCCCTTGTCGTTTGAGGTTTTGATCTCTGGGTAAAGAGGCCGTTTATCT 360 TTGTAAACACGAAACATTTTTGCTTTCTCCAGTTTTCTGTTAATGGCGAAAGAATGGAAG 420 CGAATAAAGTTTTACTGATTTTTGAGACACTAGCACCTAGCGCTTTCATTATTGAAACGT 480 CCCGTGTGGGAGGGGCGGGTCTGGGTGCGGCTGCCGCATGACTCGTGGTTCGGAGGCCCA 540 CGTGGCCGGGGCGGGGACTCAGGCGCCTGGCAGCCGACTGATTACGTAGCGGGCGGGGCC 600 GGAAGTGCCGCTCCTTGGTGGGGGCTGTTCATGGCGGTTCCGGGGTCTCCAACATTTTTC 660 CCGGTCTGTGGTCCTAAATCTGTCCAAAGCAGAGGCAGTGGAGCTTGAGGTTCTTGCTGG 720 TGTGAAATGACTGAGTACAAACTGGTGGTGGTTGGAGCAGGTGGTGTTGGGAAAAGCGCA 780 CTGACAATCCAGCTAATCCAGAACCACTTTGTAGATGAATATGATCCCACCATAGAGGAT 840 TCTTACAGAAAACAAGTGGTTATAGATGGTGAAACCTGTTTGTTGGACATACTGGATACA 900 GCTGGACAAGAAGAGTACAGTGCCATGAGAGACCAATACATGAGGACAGGCGAAGGCTTC 960 CTCTGTGTATTTGCCATCAATAATAGCAAGTCATTTGCGGATATTAACCTCTACAGGGAG 1020 CAGATTAAGCGAGTAAAAGACTCGGATGATGTACCTATGGTGCTAGTGGGAAACAAGTGT 1080 GATTTGCCAACAAGGACAGTTGATACAAAACAAGCCCACGAACTGGCCAAGAGTTACGGG 1140 ATTCCATTCATTGAAACCTCAGCCAAGACCAGACAGGGTGTTGAAGATGCTTTTTACACA 1200 CTGGTAAGAGAAATACGCCAGTACCGAATGAAAAAACTCAACAGCAGTGATGATGGGACT 1260 CAGGGTTGTATGGGATTGCCATGTGTGGTGATGTAACAAGATACTTTTAAAGTTTTGTCA 1320 GAAAAGAGCCACTTTCAAGCTGCACTGACACCCTGGTCCTGACTTCCTGGAGGAGAAGTA 1380 TTCCTGTTGCTGTCTTCAGTCTCACAGAGAAGCTCCTGCTACTTCCCCAGCTCTCAGTAG 1440 TTTAGTACAATAATCTCTATTTGAGAAGTTCTCAGAATAACTACCTCCTCACTTGGCTGT 1500 CTGACCAGAGAATGCACCTCTTGTTACTCCCTGTTATTTTTCTGCCCTGGGTTCTTCCAC 1560 AGCACAAACACACCTCAACACACCTCTGCCACCCCAGGTTTTTCATCTGAAAAGCAGTTC 1620 ATGTCTGAAACAGAGAACCAAACCGCAAACGTGAAATTCTATTGAAAACAGTGTCTTGAG 1680 CTCTAAAGTAGCAACTGCTGGTGATTTTTTTTTTCTTTTTACTGTTGAACTTAGAACTAT 1740 GCCTAATTTTTGGAGAAATGTCATAAATTACTGTTTTGCCAAGAATATAGTTATTATTGC 1800 TGTTTGGTTTGTTTATAATGTTATCGGCTCTATTCTCTAAACTGGCATCTGCTCTAGATT 1860 CATAAATACAAAAATGAATACTGAATTTTGAGTCTATCCTAGTCTTCACAACTTTGACGT 1920 AATTAAATCCAACTTTTCACAGTGAAGTGCCTTTTTCCTAGAAGTGGTTTGTAGACTCCT 1980 TTATAATATTTCAGTGGAATAGATGTCTCAAAAATCCTTATGCATGAAATGAATGTCTGA 2040 GATACGTCTGTGACTTATCTACCATTGAAGGAAAGCTATATCTATTTGAGAGCAGATGCC 2100 ATTTTGTACATGTATGAAATTGGTTTTCCAGAGGCCTGTTTTGGGGCTTTCCCAGGAGAA 2160 AGATGAAACTGAAAGCATATGAATAATTTCACTTAATAATTTTTACCTAATCTCCACTTT 2220 TTTCATAGGTTACTACCTATACAATGTATGTAATTTGTTTCCCCTAGCTTACTGATAAAC 2280 CTAATATTCAATGAACTTCCATTTGTATTCAAATTTGTGTCATACCAGAAAGCTCTACAT 2340 TTGCAGATGTTCAAATATTGTAAAACTTTGGTGCATTGTTATTTAATAGCTGTGATCAGT 2400 GATTTTCAAACCTCAAATATAGTATATTAACAAATT2436 (2) INFORMATION FOR SEQ ID NO:17: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2977 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17: CCGAATGTGACCGCCTCCCGCTCCCTCACCCGCCGCGGGGAGGAGGAGCGGGCGAGAAGC 60 TGCCGCCGAACGACAGGACGTTGGGGCGGCCTGGCTCCCTCAGGTTTAAGAATTGTTTAA 120 GCTGCATCAATGGAGCACATACAGGGAGCTTGGAAGACGATCAGCAATGGTTTTGGATTC 180 AAAGATGCCGTGTTTGATGGCTCCAGCTGCATCTCTCCTACAATAGTTCAGCAGTTTGGC 240 TATCAGCGCCGGGCATCAGATGATGGCAAACTCACAGATCCTTCTAAGACAAGCAACACT 300 ATCCGTGTTTTCTTGCCGAACAAGCAAAGAACAGTGGTCAATGTGCGAAATGGAATGAGC 360 TTGCATGACTGCCTTATGAAAGCACTCAAGGTGAGGGGCCTGCAACCAGAGTGCTGTGCA 420 GTGTTCAGACTTCTCCACGAACACAAAGGTAAAAAAGCACGCTTAGATTGGAATACTGAT 480 GCTGCGTCTTTGATTGGAGAAGAACTTCAAGTAGATTTCCTGGATCATGTTCCCCTCACA 540 ACACACAACTTTGCTCGGAAGACGTTCCTGAAGCTTGCCTTCTGTGACATCTGTCAGAAA 600 TTCCTGCTCAATGGATTTCGATGTCAGACTTGTGGCTACAAATTTCATGAGCACTGTAGC 660 ACCAAAGTACCTACTATGTGTGTGGACTGGAGTAACATCAGACAACTCTTATTGTTTCCA 720 AATTCCACTATTGGTGATAGTGGAGTCCCAGCACTACCTTCTTTGACTATGCGTCGTATG 780 CGAGAGTCTGTTTCCAGGATGCCTGTTAGTTCTCAGCACAGATATTCTACACCTCACGCC 840 TTCACCTTTAACACCTCCAGTCCCTCATCTGAAGGTTCCCTCTCCCAGAGGCAGAGGTCG 900 ACATCCACACCTAATGTCCACATGGTCAGCACCACGCTGCCTGTGGACAGCAGGATGATT 960 GAGGATGCAATTCGAAGTCACAGCGAATCAGCCTCACCTTCAGCCCTGTCCAGTAGCCCC 1020 AACAATCTGAGCCCAACAGGCTGGTCACAGCCGAAAACCCCCGTGCCAGCACAAAGAGAG 1080 CGGGCACCAGTATCTGGGACCCAGGAGAAAAACAAAATTAGGCCTCGTGGACAGAGAGAT 1140 TCAAGCTATTATTGGGAAATAGAAGCCAGTGAAGTGATGCTGTCCACTCGGATTGGGTCA 1200 GGCTCTTTTGGAACTGTTTATAAGGGTAAATGGCACGGAGATGTTGCAGTAAAGATCCTA 1260 AAGGTTGTCGACCCAACCCCAGAGCAATTCCAGGCCTTCAGGAATGAGGTGGCTGTTCTG 1320 CGCAAAACACGGCATGTGAACATTCTGCTTTTCATGGGGTACATGACAAAGGACAACCTG 1380 GCAATTGTGACCCAGTGGTGCGAGGGCAGCAGCCTCTACAAACACCTGCATGTCCAGGAG 1440 ACCAAGTTTCAGATGTTCCAGCTAATTGACATTGCCCGGCAGACGGCTCAGGGAATGGAC 1500 TATTTGCATGCAAAGAACATCATCCATAGAGACATGAAATCCAACAATATATTTCTCCAT 1560 GAAGGCTTAACAGTGAAAATTGGAGATTTTGGTTTGGCAACAGTAAAGTCACGCTGGAGT 1620 GGTTCTCAGCAGGTTGAACAACCTACTGGCTCTGTCCTCTGGATGGCCCCAGAGGTGATC 1680 CGAATGCAGGATAACAACCCATTCAGTTTCCAGTCGGATGTCTACTCCTATGGCATCGTA 1740 TTGTATGAACTGATGACGGGGGAGCTTCCTTATTCTCACATCAACAACCGAGATCAGATC 1800 ATCTTCATGGTGGGCCGAGGATATGCCTCCCCAGATCTTAGTAAGCTATATAAGAACTGC 1860 CCCAAAGCAATGAAGAGGCTGGTAGCTGACTGTGTGAAGAAAGTAAAGGAAGAGAGGCCT 1920 CTTTTTCCCCAGATCCTGTCTTCCATTGAGCTGCTCCAACACTCTCTACCGAAGATCAAC 1980 CGGAGCGCTTCCGAGCCATCCTTGCATCGGGCAGCCCACACTGAGGATATCAATGCTTGC 2040 ACGCTGACCACGTCCCCGAGGCTGCCTGTCTTCTAGTTGACTTTGCACCTGTCTTCAGGC 2100 TGCCAGGGGAGGAGGAGAAGCCAGCAGGCACCACTTTTCTGCTCCCTTTCTCCAGAGGCA 2160 GAACACATGTTTTCAGAGAAGCTCTGCTAAGGACCTTCTAGACTGCTCACAGGGCCTTAA 2220 CTTCATGTTGCCTTCTTTTCTATCCCTTTGGGCCCTGGGAGAAGGAAGCCATTTGCAGTG 2280 CTGGTGTGTCCTGCTCCCTCCCCACATTCCCCATGCTCAAGGCCCAGCCTTCTGTAGATG 2340 CGCAAGTGGATGTTGATGGTAGTACAAAAAGCAGGGGCCCAGCCCCAGCTGTTGGCTACA 2400 TGAGTATTTAGAGGAAGTAAGGTAGCAGGCAGTCCAGCCCTGATGTGGAGACACATGGGA 2460 TTTTGGAAATCAGCTTCTGGAGGAATGCATGTCACAGGCGGGACTTTCTTCAGAGAGTGG 2520 TGCAGCGCCAGACATTTTGCACATAAGGCACCAAACAGCCCAGGACTGCCGAGACTCTGG 2580 CCGCCCGAAGGAGCCTGCTTTGGTACTATGGAACTTTTCTTAGGGGACACGTCCTCCTTT 2640 CACAGCTTCTAAGGTGTCCAGTGCATTGGGATGGTTTTCCAGGCAAGGCACTCGGCCAAT 2700 CCGCATCTCAGCCCTCTCAGGAGCAGTCTTCCATCATGCTGAATTTTGTCTTCCAGGAGC 2760 TGCCCCTATGGGGCGGGCCGCAGGGCCAGCCTGTTTCTCTAACAAACAAACAAACAAACA 2820 GCCTTGTTTCTCTAGTCACATCATGTGTATACAAGGAAGCCAGGAATACAGGTTTTCTTG 2880 ATGATTTGGGTTTTAATTTTGTTTTTATTGCACCTGACAAAATACAGTTATCTGATGGTC 2940 CCTCAATTATGTTATTTTAATAAAATAAATTAAATTT2977 (2) INFORMATION FOR SEQ ID NO:18: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2517 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18: GGAATTCCGTGGCCGGGACTTTGCAGGCAGCGGCGGCCGGGGGCGGAGCGGGATCGAGCC 60 CTCGCCGAGGCCTGCCGCCATGGGCCCGCGCCGCCGCCGCCGCCTGTCACCCGGGCCGCG 120 CGGGCCGTGAGCGTCATGGCCTTGGCCGGGGCCCCTGCGGGCGGCCCATGCGCGCCGGCG 180 CTGGAGGCCCTGCTCGGGGCCGGCGCGCTGCGGCTGCTCGACTCCTCGCAGATCGTCATC 240 ATCTCCGCCGCGCAGGACGCCAGCGCCCCGCCGGCTCCCACCGGCCCCGCGGCGCCCGCC 300 GCCGGCCCCTGCGACCCTGACCTGCTGCTCTTCGCCACACCGCAGGCGCCCCGGCCCACA 360 CCCAGTGCGCCGCGGCCCGCGCTCGGCCGCCCGCCGGTGAAGCGGAGGCTGGACCTGGAA 420 ACTGACCATCAGTACCTGGCCGAGAGCAGTGGGCCAGCTCGGGGCAGAGGCCGCCATCCA 480 GGAAAAGGTGTGAAATCCCCGGGGGAGAAGTCACGCTATGAGACCTCACTGAATCTGACC 540 ACCAAGCGCTTCCTGGAGCTGCTGAGCCACTCGGCTGACGGTGTCGTCGACCTGAACTGG 600 GCTGCCGAGGTGCTGAAGGTGCAGAAGCGGCGCATCTATGACATCACCAACGTCCTTGAG 660 GGCATCCAGCTCATTGCCAAGAAGTCCAAGAACCACATCCAGTGGCTGGGCAGCCACACC 720 ACAGTGGGCGTCGGCGGACGGCTTGAGGGGTTGACCCAGGACCTCCGACAGCTGCAGGAG 780 AGCGAGCAGCAGCTGGACCACCTGATGAATATCTGTACTACGCAGCTGCGCCTGCTCTCC 840 GAGGACACTGACAGCCAGCGCCTGGCCTACGTGACGTGTCAGGACCTTCGTAGCATTGCA 900 GACCCTGCAGAGCAGATGGTTATGGTGATCAAAGCCCCTCCTGAGACCCAGCTCCAAGCC 960 GTGGACTCTTCGGAGAACTTTCAGATCTCCCTTAAGAGCAAACAAGGCCCGATCGATGTT 1020 TTCCTGTGCCCTGAGGAGACCGTAGGTGGGATCAGCCCTGGGAAGACCCCATCCCAGGAG 1080 GTCACTTCTGAGGAGGAGAACAGGGCCACTGACTCTGCCACCATAGTGTCACCACCACCA 1140 TCATCTCCCCCCTCATCCCTCACCACAGATCCCAGCCAGTCTCTACTCAGCCTGGAGCAA 1200 GAACCGCTGTTGTCCCGGATGGGCAGCCTGCGGGCTCCCGTGGACGAGGACCGCCTGTCC 1260 CCGCTGGTGGCGGCCGACTCGCTCCTGGAGCATGTGCGGGAGGACTTCTCCGGCCTCCTC 1320 CCTGAGGAGTTCATCAGCCTTTCCCCACCCCACGAGGCCCTCGACTACCACTTCGGCCTC 1380 GAGGAGGGCGAGGGCATCAGAGACCTCTTCGACTGTGACTTTGGGGACCTCACCCCCCTG 1440 GATTTCTGACAGGGCTTGGAGGGACCAGGGTTTCCAGAGTAGCTCACCTTGTCTCTGCAG 1500 CCCTGGAGCCCCCTGTCCCTGGCCGTCCTCCCAGCCTGTTTGGAAACATTTAATTTATAC 1560 CCCTCTCCTCTGTCTCCAGAAGCTTCTAGCTCTGGGGTCTGGCTACCGCTAGGAGGCTGA 1620 GCAAGCCAGGAAGGGAAGGAGTCTGTGTGGTGTGTATGTGCATGCAGCCTACACCCACAC 1680 GTGTGTACCGGGGGTGAATGTGTGTGAGCATGTGTGTGTGCATGTACCGGGGAATGAAGG 1740 TGAACATACACCTCTGTGTGTGCACTGCAGACACGCCCCAGTGTGTCCACATGTGTGTGC 1800 ATGAGTCCATCTCTGCGCGTGGGGGGGCTCTAACTGCACTTTCGGCCCTTTTGCTCGTGG 1860 GGTCCCACAAGGCCCAGGGCAGTGCCTGCTCCCAGAATCTGGTGCTCTGACCAGGCCAGG 1920 TGGGGAGGCTTTGGCTGGCTGGGCGTGTAGGACGGTGAGAGCACTTCTGTCTTAAAGGTT 1980 TTTTCTGATTGAAGCTTTAATGGAGCGTTATTTATTTATCGAGGCCTCTTTGGTGAGCCT 2040 GGGGAATCAGCAAAAGGGGAGGAGGGGTGTGGGGTTGATACCCCAACTCCCTCTACCCTT 2100 GAGCAAGGGCAGGGGTCCCTGAGCTGTTCTTCTGCCCCATACTGAAGGAACTGAGGCCTG 2160 GGTGATTTATTTATTGGGAAAGTGAGGGAGGGAGACAGACTGACTGACAGCCATGGGTGG 2220 TCAGATGGTGGGGTGGGCCCTCTCCAGGGGGCCAGTTCAGGGCCCAGCTGCCCCCCAGGA 2280 TGGATATGAGATGGGAGAGGTGAGTGGGGGACCTTCACTGATGTGGGCAGGAGGGGTGGT 2340 GAAGGCCTCCCCCAGCCCAGACCCTGTGGTCCCTCCTGCAGTGTCTGAAGCGCCTGCCTC 2400 CCCACTGCTCTGCCCCACCCTCCAATCTGCACTTTGATTTGCTTCCTAACAGCTCTGTTC 2460 CCTCCTGCTTTGGTTTTAATAAATATTTTGATGACGTTAAAAAAAGGAATTCGATAT251 7 (2) INFORMATION FOR SEQ ID NO:19: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 35100 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19: AATTCACCAGTGAAGCCATCTGGTCCTGGGCTTTGCTTTGTCGGGAGGTTTTTGATTACT 60 GATTAAATTTCTTTTCTTGTTATAGGTTTATTTGGATTTTCTTTTTCTTCTTGAGTCAGC 120 TTTGATTGACATTCATGATTGCTAAAGGTTCAAAACACTTTTCTGAAAAAGAAAGTACAT 180 ATATACACTCATAAATATACATACAAACACACACATACACACCACACACACACCTGAGTA 240 CACGGGAATGATCATTTTCCTGGATCAATGTTATATCAGGATTTTTCAATTTCAAGAAGG 300 AACTTTAGGCTGGGTATAGTGGCTCATACCTATAATCCCAGTACTTTGGGAAGCCAAGGT 360 ATGCGAATCACTTGAGCTCAGGGGTTTGAGACCAGCCTGGACAACATGGTGAAACCCCAT 420 GTCTACCAAAAATACAGAAATTTGCTAGGAATGGTGGCACATGCCCCTGTAGTCCCAACT 480 ACTCAGGAGGATGAGGTAGGAGGATGGCTTGAGTCCGGGAGGTGGAGGTTGCAGTGAGCC 540 GAGATCACACTACTGCACTCCAGCCTGGGTGACAGAACCAAACCCTGTCTCAGAAAAAAA 600 AAAAGAAAAAAAGAAGAAGAAATGACCATGTTCTTTAGAGATAAGAAGTAAAATACTAAG 660 CGAATCAACTAAAAGAGGTAAAAGCAATTGCCTCCAGGAAAAGAGGGAGCAAAGGAATGC 720 TATATATTTTAAGAATTATGCAGAACAATTAGATTCTTTGTAAAAATAAATAAACAATGT 780 AAGTAACGCACAAAAGATAGTTTTATAACCAGACTGCTGGGATCCAAATCCTATCTCCAC 840 CATTTGGTAGCTGTTTGACTATGGACAAGCTTAAGGCACTTGATCTCTCTGAGCTTTAGT 900 TTTCCCATCTGTGAAATGAGAATGACAATAGTACTTACCTACATAAAGTTTTGCAGTACT 960 AAAGGAGACAGTGAATGTAAAAGGTTTGGCTAGTAAATGTCCTGTAAAAGGAAGCTTATT 1020 GCCAATATTATCAGGCTCTCCCAGACCAACCTGTATACAGGAAGAAAACAAACTCCGTTT 1080 CTCCTATAGTCTCACAACACAAAATACTTCTGACCCCAGATGTAGAGGATGGGGCATATT 1140 TCCCCATACACCAAGCAATCAACCAATTGTTCAGATTCTGCAGCAGACACGAATCTGGTG 1200 CCCTCCGATTCAATTTGAACACTATATTTACCTAGAGATAACGTCAGATCTCACAGCTTG 1260 AAGGCTTGAGCCAGGAGTTTGAGGCTGCAGTGAGCTATGATCGAGCCACAGAGCTCCAGC 1320 CTGGGCAACAGAGTGAAACTGCGTCTCTAAAATAATAATAATAAATTTTTAAAAGATATG 1380 CATTACTTTGGAGATTCCAAGGATTTTAGGAGTTGTAAGCCAGGACATCAGGGTAAAGAA 1440 AAAATATATATGTCACAATATCATGCAACCTAACTTCTCTTTGGGATCTGCCAGAGCCAC 1500 CTGATCACTCTGAAGACCCTCATTTGTGCTACTGACTAACGGTCTGGCTGCTCTTGGACA 1560 TGTCTCTTCTCCCAAGACCCCTTGAAGATGGCTTTAGAAGGGCCCCAAACTTAGCTAGCT 1620 CCCCCCAAGCTCAGGCTGGCCCTGCCCCAGACTGCGACCCCTCCCTCTTGGGTTCAAGGC 1680 TTTGTTTTCTTCTTAAAGACCCAAGATTTCCAAACTCTGTGGTTGCCTTGCCTAGCTAAA 1740 AGGGGAAGAAGAGGATCAGCCCAAGGAGGAGGAAGAGGAAAACAAGACAAACAGCCAGTG 1800 CAGAGGAGAGGAACGTGTGTCCAGTGTCCCGATCCCTGCGGAGCTAGTAGCTGAGAGCTC 1860 TGTGCCCTGGGCACCTTGCAGCCCTGCACCTGCCTGCCACTTCCCCACCGAGGCCATGGG 1920 CCCAGGAGTTCTGCTGCTCCTGCTGGTGGCCACAGCTTGGCATGGTAAGAGCAGAACGGG 1980 GGGTGGGGGACTTTGTTGGGGTGTGATGGAGAAGACCCCTGTGAAAGGATTCAGTCCTTG 2040 CCCCTCACTGGGTGTCCTCAGGCTGTTTTAGTCTCCCCAACACTGGACTGCAGGCTTGTG 2100 GGTATCTGCTTTGGAGAGGTAGTGGGGTGAAAAGAGATGGGTGTGGTGGAACTGGTCCAC 2160 CTGGTGCTGTGGATCTGTCCCAGCTCTGCCAGCGACTCACTGTGTGTCCTGAGCAAGCCT 2220 CTGATACTCTTGAGGCTTCAGTGTCCACTTCTATTCAATTGCAGGTGTTGGGGGCAGGGG 2280 GACAGTGATAGACTAGACCAGAGCAGTGCTTTTCATACTTTCCTGTGCATACAAGTTACC 2340 TGAGGATTTTGTTACAATGCAGATTCAGACTCAGTCGGTCTCAGGTGCGACCTGAGATTC 2400 TGTATATCCAACACACTCCTGGGAGATGTGAGATGCCGGCACTGCTGGTCCAGACCTACA 2460 CTGAGTTGGGAGGACCTGGAGAGCTCCTGATGGCTCTGGCAGCTCTGCCAGCCTGTGATT 2520 CGATGATTCTATGCAAGATCTGATTTGGAAGGGCCTGATAGGGGTGGTGGTTCTTCCTTG 2580 GGTGGCTTGTGTAAGGGGTCAGAGGGGAGAGACAAGAGGTTGGCCTCTCTGGCCCAGGGC 2640 TCAGGAGAGGGGAATTCGGGGTGAAATAGGTATAGGGCTAGAGGAGGGATTGGGAAGAGG 2700 CCAGTGAGGGTCTCCTGGACCAGAGCCCTCCCAGACACAGGCTGCCAAGTCTCAGGAGGT 2760 CCCCAGGCTGTAGCAGTTCTGCAGAATTTCCATCTGGGAGGGAACATGACTAGAGGTGAG 2820 GGGCTGCTGTGCTTGGCTTGTTGGCCCAACAAACACATTTCTATTGCCTGCTTATTCAAA 2880 GGGACCTTGGGGGAGGATGGGGATTGAAGGGGAGAAAGGACAGCCTCATACTGGCCTCTT 2940 CACAGAAGGACCCTAAGGCCGTGGCGCTTCTGGTCCCTGATGAGGAGGAGATGGCCCACT 3000 GACCATCCTTCTCTGGCCCAGGCAATCACACTGAGCTTGAGTATTTGGGTTTTTTTTTTT 3060 TTTTTCCTGAGACAGAGTCTCTCTCTGTCACCAGGCTGGAGTACAGTGGCACAATCTCGG 3120 CTCACTGCAACCTCCACCTCCCGGGTTCAAGTGTTTCTCCTGTCTCAGCCTCCCAAGCTG 3180 GGATTACAGGCATACACCATCATGACTGGCTAATTTTTGTATTTTTAGTAGAGATGGGAT 3240 TTCACCATGTTGGCCAAGCTGGTCTCGAACTCCTGACCTCAGGTGATCCACCTGCCTTGG 3300 CCTCCCAAAGTGTTGGGATTACTGGTGTGAGTCACGGCGCCCGGCCTGGACTTCTTATTT 3360 TGCAATGTAACTTACATGCAGTAGAAAGCACAGGTTCTTAAGTTCAATGAGGTCTGACAA 3420 ATGCACACACAGTGTACCCGCCACCCCCTTCATCTCAGAGAGTCCCACAGGTTTGATTTC 3480 ACTGCCTTGTCCTATCCTTACACCCACAACCTGCCTGTGGGGCAAAAACGGAAAAGTATC 3540 TGAGCCAGGTCTCAATTTAATTTTATTTTTTTTATTGAGATGGAGTCTTGTGGCCAGGCA 3600 TGGTGGCTCACACCTGTAATCCCAGCACTCTGGGAGGCCGAGGCGGGTGGATCACAAGAT 3660 CAGGAGTTTCAGACCAGCCTCGCCAATATGGTGAAGCCCCCTCTCTACTAAAAAATACAA 3720 AAATTAGCCGGGTGTGGTGGTGGGTTCCTGTAGTTCCAGCTACTCAGGAGGCTGAGGTGG 3780 GAGAATCACTTGAACCCGGGAGGCAGAGGTTGCAGTGAGCTGAGATCATGCCACTGCACT 3840 CCAGCCTAGGCGACAGAGCAAGACTCCATCTCCTTCCTTTCTTTCTTCCTTCCTTCCTTC 3900 CTTCCTTCCTTCCTTCCTTCCTTCCTTCCTTCCTTCCTTCCTTCCTTCTTTCTTTCTTTC 3960 TTTCTTTCTTTCTTTCTTTCTTTCTTTCTTTCTTTTTTCTATCTTTTTGAGACCGAGTCT 4020 TGCTCTGTTGCCCAGGCTGGAGTGCAATGGCATGGATCTCGGCTCACTGCAACCTCCGCC 4080 TCCGGGGTTCAAGCAATTCTGCCACTCCTGAGTAGCTGTGATTACTGGTGCCTGCCACCA 4140 CACCCAGCTAATTTTTTTATTTTTGGTAGAGACAGGGTTTTATCATGCTGGCCATGCTGG 4200 TCTCGAACTCCTGAACTCAAGCGATCCCCCTGCCTTGGCGTCCCAAAGTGCTGGGATTAC 4260 AGGCATGAGCCACTGTGCCTGGCTTCAATCAATTTAGAAGTTTATTTTGCCAAGGTTAAG 4320 GACATGCTGGCGAGAAAAAAACATGGAGTCACAAAAACATTCTGTGGTCTGTGCCATTCT 4380 GGATGAATTCGAGGGCTTTAATATTTAAAGGGGAAAGTGGGCTGGAGGGGAAAAGGGGAG 4440 GTTGTGGTAATCCACATGTTGCAAAAGAAAAGCAGCAGGTAGGGGAACAGTCAATTATCT 4500 CGGTTCAGTAAATTGGCTCTTTACATAGGGAAAGTGAACATAGAGGAGCTGCCTGTGGGA 4560 TATTTTACCTTTTATCTGTCGCTATCTGCTTAGGAATAAAAGGCAAGGCAGCTTCTTGCA 4620 TGACTCAGTTTCCAGCTTGATTTTTCCTTTTGGCAGAGTGAATTAGGGTCCCAAGTTTTT 4680 ATTTTCCCTTCACAGGGGCATGGTGTGTGGGAGGGGGGCCAGATGGTTTTCCAGGGTCCA 4740 GTCCCAAGAGAAAGAAGAGATGGGGAGGCTGGAAACCTAAGTTTTCAGCCCAACAGACCA 4800 ATGATGAGTGGATGAGGGGCCACTGTGAGGAGACTGGGGATGGTATTGGAGGACCCTAGA 4860 GAGAGAGGGGGGCTCTCTCTTCATTACTGCGATGAGATCCTGGGCTGAAGAGGGGCTGTG 4920 TCCAGCCTTAGTGTGCAGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG 4980 TGTGTGTGTTGGGAGAGAAGAGTAGAGATTGGGGCACATTCTGGAAGTGATGAGGGAGGG 5040 GCTTCCAGGCAAGTGGGAGCTAGTGGAGAGGTGTGGGGCATGGGGAGAATTGGGGAGTGG 5100 AGATGAGAGGGGGGAAGAATGGACAGGCACAGAAGGGGACCTCAGTTAATGTTCATAAGC 5160 CCATGCCCCCACCCCGAGGAGGATGGGGGCCAAGCCGGCTTCCTTCCCTGCTAGCCAAGC 5220 CAGCAGGGGAAGTTGGCTGCGGAAGTTGCGGGTATCAGCCTTATCCTGCGTGAATACCTG 5280 GGACAATAGGATAGGACAAAATAGGGCAGACACCGCTCCCTGACCACATTTCCTGGAGGC 5340 CAAGGCAGGGTCTAGAGAGACAGGCTGGGGGAAGGGATGGGAGAAGCCCACTGTAAGGTG 5400 TGAGGCAGGTGTAAAAAAGGAACAAATGGAATCACAGAATCCAAGGTTAAAATCTTGAGC 5460 GATCAGAGTTGGCCCAGAAGGGACATTAGAAATGTAGCAATTAAAGCAGGTGCCCAGGGC 5520 AGGAGTAGTTCTATACATCATCTCACTCAACCTTCAGCTGAAGTTTTTGGGGTGGGAGCT 5580 GGGATTATTCCCATCAGACAGAAGAATAGCCTGAGGCTCAAAGAGGTTAAGAAACTAACC 5640 CAGCTGGTAAGGGAAGAACCAAGATCCAAACCCAAGTTGGTGTGAGCCCACACTCCAAGC 5700 TGTTTCCTGCTATAAAACCCCGGCCTGGGGGCCCTAGATTGCTGCAGCAGTGATAGGGCA 5760 GCCCCAGCTCTGTTGAGATTTGCTAAAAAGGCTGCTAGAAATGACACTTGTCCCTCTTCC 5820 TGGCAGTTGCACTGCATAGGAGGGCTACAACCCCAGGTGGCAGGCTTGGCAGTATTCACA 5880 ATTCACTCAATCCCGTTTGCTGATCAGAGTCTTGGGGAGAAGGGATGCACATTCTGATGA 5940 ATACAAAATCAAAACGTGAATTAAGCCATCCTGAAAGGACTTGAGAGAGGAAACCTTTCC 6000 AATTCTGGGCTCTATGGTGGGGCAGGGGGAATTTCCATTTCAAGGGGGTTTGCAGAGAAC 6060 AATGGAGATACCCTGAATTCACCGAAAGCCCTCGGGGTGGCCTGTCATTGTGCCCCCATC 6120 ACTGGGAAGAGGAAGGGCCAGAGCTGAGGAGTTGGATGGCCAGGGTCAGCCAGTGGGTCA 6180 GCGTCAGAGCCCAGCCTCACAGCTGCCCCGCAAGTGGCACTCCCTCTCCCTGCCTGGAGA 6240 GAGGAGAGTGGCTAGGAGGCTGGGGAAGCAGAAGTGAGAACATCCCTGTAGAAGGGCCAC 6300 AGGCTGAGCGGAAACCGGGGGCTGAGCCTGACGCCAACAATGTGTTTCCGCCCACACAGG 6360 CTGGGGGGCGCCTGGCAGCCCCTCGGAGGCTTGAATCAGCTCTCACTTCCCTCCTTTGCC 6420 CCTATTTTAGGCCCTGGAAAAATGCTGACGCTGCAGAGGCAACGGGCCTTCTTCCCGGAC 6480 AGCCTGATAGGGGTTTCAAGTTCTCTTTTCTCCTTCAAGAAAATTTTCCTTAAAAGAGAT 6540 TGGCTTCCCAGTAAACACAGATGTGTGGGGGTGCCGGGGTGAGCTGCTGGGTGTAGACTA 6600 GGTAATAAACATAGTGACTAACTCTTACTGAGCCATTTATTTGGTGACAGGTGATGTTCT 6660 AAAGTCTTCCCATGCATTTAAAATGCCTAACATACCAATGAGTGGGTACGATGATTGTCC 6720 CTGTTTTATAGGTGGGGAAACTGAGGCATGGCACCTCCCCATCCCACTGTGCTGCAGACC 6780 AGATGTCCATTGGTGGGAGCGGGCACACCAGGAGATTCTTGGGACCTCTCTAACTCTGCT 6840 GGGCTAAGATCCTACATCTCTTTTTTTTTCTTTCCCATATGAATTAAGCTGAGGACTTGG 6900 CCGTGAACATTCCATTCATTTGTTTCTTCATTCGGTGGTAGAAATACATCCACTTTGTAC 6960 ACAGGGTTAAAAGAGTCCATTCCTGGGGAGTAGAAAGATGGCATCACAGCAGGGAAGACT 7020 GAGGCAGGAGGCTGAGGACCCCAGGGGGACAGAGGCCTGGGTGAGAGGCTGAGCAAGCTG 7080 CAAGCCCCCTTTCTCAGAGGAGGGACCTCCTGGACATCAGAGACATCAGTCTGTCCCTGA 7140 GCAGGTTGAGGGTTAGGAGCTGAGCAAATGACCAGGGGGCAGGGGCTCGTTCAAGGTGGT 7200 CCCTTGATGGCACAGCACCATCCCTGCCAAGCTACCACCCATCTCAGAGTCAGGACGGCC 7260 CAAGGGGCGCATCCTAGACCTCACTTCTGTCTGCTGTCCCTCTCTCCCACCAGGTCAGGG 7320 AATCCCAGTGATAGAGCCCAGTGTCCCCGAGCTGGTCGTGAAGCCAGGAGCAACGGTGAC 7380 CTTGCGATGTGTGGGCAATGGCAGCGTGGAATGGGATGGCCCCCCATCACCTCACTGGAC 7440 CCTGTACTCTGATGGCTCCAGCAGCATCCTCAGCACCAACAACGCTACCTTCCAAAACAC 7500 GGGGACCTATCGCTGCACTGAGCCTGGAGACCCCCTGGGAGGCAGCGCCGCCATCCACCT 7560 CTATGTCAAAGGTGAGGAGTCTGAGCCTCCTCCCAAGAGGCCTGACCCGGCAGGCCCCAC 7620 TACAATGGGCCCTAAAATTAACAATCGTAACAATTCAGCTCTGCATTTACTGAGTGCTGG 7680 CTATGAGCAAGGACCTGGAAGAGCTGCTAATGTAATGCAGTCCTCACAACAACCCTGCAA 7740 GTCGGGTCTATGATGATGCATTTTCTAGAAGTGCAGGGAGGTTATCCAAGGTCACACAGC 7800 CTCACATAGTGGGACTAGACTGGAGCCCAGGTGCGCCTGACTCTGGAGCCACCACGCTGA 7860 AGCATCCGCTGAACTGTCCTGGCGTGGTGTGACCTCAGATGAATGATCAGCCTCTCTGAG 7920 CTTCCTTGTCACCTATGTCCAGGTACTCCTTGGCCCAGTGGAGGGAGGGCAGTTGTAACC 7980 CTGTGCCCTCCTCTACTCTAGACCCTGCCCGGCCCTGGAACGTGCTAGCACAGGAGGTGG 8040 TCGTGTTCGAGGACCAGGACGCACTACTGCCCTGTCTGCTCACAGACCCGGTGCTGGAAG 8100 CAGGCGTCTCGCTGGTGCGTGTGCGTGGCCGGCCCCTCATGCGCCACACCAACTACTCCT 8160 TCTCGCCCTGGCATGGCTTCACCATCCACAGGGCCAAGTTCATTCAGAGCCAGGACTATC 8220 AATGCAGTGCCCTGATGGGTGGCAGGAAGGTGATGTCCATCAGCATCCGGCTGAAAGTGC 8280 AGAAAGGTGCGTGGGGCATGGGGACCGGCAGCCAGGCCTGAAGAGTGGGGACAGAGAGCC 8340 GGCGGCCACATGGGTGGTGACTGGGGACTGGGTGTGATGGGGGGCAGTGGGATGTCCTCT 8400 TTCTTTCACTTCTTCCCCTCAATGGTTCCACGATCATCTATGGGGCAGGACTGACAAGGT 8460 GTCGGGGCAGGGAGACAAACCACATGTGAGCAAATAACTCAGTGGGCAAGGTCATCTCAG 8520 GTCATTGGACATGCTACAAAAATAAACATTCAACATGGTAGCTGAATAAGGAGTGTGTAG 8580 GGCGGGGAGCCTCACTGAGAAGGAAACACTTTATTAGAGCGGAAATCTGAATGACATGAA 8640 GAAGGTGGCTGTGCAAAGATCTGCTTCAGCAGGGGGACAGTGAGTACCAAGTGGTGAGGT 8700 GGGGACAGGCTCTGAATGTTCTAGGTATGGAAAGAGGACGGAAGCTCAGCCTCAGACATG 8760 GATTTCCCACTGGGGGCCTGCCTAAGGCCAAGTGCTGGGCATGTGTAGGAGGGATGCTGA 8820 GCCAAGAGGCAGGGAGGAGATGGTGGGTGCGTGTGATGGCTCTCGCGGTGGCCAGGTAAC 8880 AGTGGAGGTGGAGTCTCACCCTGCTGGGATGGCAGGCAGGATTCTGGTTTCTGGGAGGAC 8940 TGGTGAGAGCAAGCAGGACCCCAGCCTGAGGACCTGGGCTTGAGACAGCAATCAGTCCCT 9000 GTAACAAGGGCCAGGGTCAGAGTGAAGCAGCTAGCCCAATGCCACTGGGATCTGAAGCCA 9060 CTAAACCTGCCTAGGGGGTCAAAGGACCCCAGCTGTGTGGGCAGAGGAGGCCATTAGGGC 9120 TCTTTCCTGGCATTTCATCCTGCAGAGCCCTGGGCTGGCCAAGAGCCAAAGGTCCTGGGC 9180 CCTAGTTCTGCCTTGACCCCCCCTCAGGGACCTTGGGTGAGTCCTTTCATGTCCCTGGGC 9240 CTTAGGAATCTGGATTAGATTATCTTTCAACAGCAGCAATGGGCATAAATATGAATTCAA 9300 GGCCTACTGTGCATCAGGCATCTTGCTGGCTGCTGGAATATTCCTGTCACGGATTTGACA 9360 TTCGACTAGAGTCTAACTATTAAATAGAAAGTAAATACAAATGTGATGAGCAAGAAACCA 9420 AGCTGGGGAGTGGCGGGCATGGAGGTGCTGGGGAGGCTAATTCATATCAGCTGGTCACAG 9480 AAGCCTTGCTGAGGAATTTTTGAGCTAAAGATCTGAAGGATGAGAACAGCCTCCCATTTG 9540 AAGTGTGGGAGGAAAGGCATTCCAGGAGGGAAAGGTGGGTGCAAAGGCCCTGTGGTAGGA 9600 AAGAGGTCCAGCGGGCTGCAGTGCAGTGAACAAGGGGTGGGGTTATCAGGGCGGTCAGAA 9660 ACAGGTTGGGCTGTGGAAGGACTTTGACTTCTTTTCTGAGAGTAATGGGAAGCCCCAAAT 9720 GTTTACAGAGGAGAGAGGCATGGTCCCATTTATATTTGTAAGAGGTCACTTTGGTGAAGA 9780 ATCTAGGTGTGGGGGGCTTGGAGGGAGGCAGGGAGGTCTCTGAGGAGGCTGGTGCAGAAG 9840 TCCAGAGTGGAGAATGGTGACGGGACTGGGGAGGGGTAGAGGTGATGGAGAAAGTAGACT 9900 TTCCAAGGTCTCTTTAGGACAGGCCTTGCAGTGGGGGGACTGGGAGCATCAAGGCTGCCT 9960 CCCAGGATTTGGGATGGGGCAGTGATGGGGACCCTGGCCTGTGTGTCCTGGCCCATGGCA 10020 GGGAGGAGAGCAATATCTCTATCATATTCAGGGAGCCTGGGTGTTCAGGGGTCTCTCCCC 10080 CGGTCTCAGTCATCCCAGGGCCCCCAGCCTTGACACTGGTGCCTGCAGAGCTGGTGCGGA 10140 TTCGAGGGGAGGCTGCCCAGATCGTGTGCTCAGCCAGCAGCGTTGATGTTAACTTTGATG 10200 TCTTCCTCCAACACAACAACACCAAGGTCAGTCCCTGCAGATCACAAGGTGAAGTCTGGC 10260 CATCCTCCCAGCACACCAGGTTTCCCATGGTGGAGTCCTGGGCCCCCAACTCCAAACTGG 10320 CTGTCTTAGCTGAAGGCACAGCTCAGACTCCAGAGAGGGGTGCAGACTCACCCGAGATCT 10380 CACTCCCAGTCAGTAGCTGACACAGAATCAGGACTCATGCTTGTGCCGCTGAACTTTGTG 10440 GGGGTGGGTGGGGGGAGGTGGTTCTCTGTCACCTTGACACATGGCCTTTGCCCCAGCCTT 10500 TAGACAAAAGCCAGAGGTGAGCTCACTTCTGATTTAGCAAGGGTTTCCTAGGCCACCATT 10560 GAAGCCCAGGAATATAACAGCTATTTCAGAAAGACATTGGGAGAGAGGGAGGAGGAGGGA 10620 GGATTCCAGGAGGGACTCACGTTGGGCTGCCTCTAAGAGCCCCCTCCCTTCCCACTGCAC 10680 CTGCCGTGTTCCAGACACAGCCCTAAGCCACTTGCATGCATATCTCATTTACTCCTCACT 10740 ACAGTCTTGGGGCAGGGAGCCAGTATTAGCCCCATTTTACAAGTGAAGCAACAGGCTCAG 10800 AGGAAAGGCAGATAGTAATCCTTAAAGGCTGAGGATTGGAACCCAGATCTTTCTAATCCC 10860 TAAACTACCTTGGTATAACATCTCCATTCCTTCTGGCTGCAGCTCGCAATCCCTCAACAA 10920 TCTGACTTTCATAATAACCGTTACCAAAAAGTCCTGACCCTCAACCTCGATCAAGTAGAT 10980 TTCCAACATGCCGGCAACTACTCCTGCGTGGCCAGCAACGTGCAGGGCAAGCACTCCACC 11040 TCCATGTTCTTCCGGGTGGTAGGTAAGCATCAGGGTGGTGGTGGACAGTCGGTAGGGATC 11100 CTGCAGGAGTGTGAGCAGAAGGGTTTTGTTGAGGAAGCTGATGTCAGGGAAGGAGACCTG 11160 CTGAGGATATCTCTGCTGGAGTTTGTTTATCCAAGGCCTGGCTAAGGAGCCACTCTCCAG 11220 GAGCTTTCCCTTACCCTCTCCTGGGATCTCTCTCCCATCTTGGAGCTCTTACAGTGCATG 11280 GCTGCATTGGGTGCACCTTAGTGCCATTTTTTGTTTATTTGGGGATTGGGGTCCAGTAGC 11340 TCCCTACTGGACTTCATTTGTTCATTCTTTCATGCATTCCTTTATGGAAACATGAAAAGA 11400 CAATGATCACCCAGTGATTATGGGGGAAGCACAAGGTGTCCTGGGAACACTGAAGAGTCC 11460 CCCCAACCCAGGCTTCGAGAAGGTGGCCTCTAAACTGGGATGGGAAGAATGAAGGTGAGT 11520 TGGCCGGGCAGAAGGGTGGGAAAGGAAGGGGAACAGCGCTTCTGGCAGAGGGAGGAACAT 11580 ATGCAAGGCTCAAAGGCAAAGAGAACATAGATCATTTGGAACACTGAAAGAACTTGACAA 11640 CAGCTGGGATGTGGAGTGGTGTGAGGAGTGGCCACAGGGGAGCAGAGGAGGTGGCAGAAG 11700 CCGGAGGTAAAGGTGTCTTAAAGTGAGAAAGAATAACTGCATCTTAACCTATTGGGAGGT 11760 CATTGTAAAGAGGAGAGTGATGGGGTCAGATTGTACAGAGGAGGCACTTCGTGGTGGTCA 11820 GGAGCACACACTCCAGGGCAGTGTTCCAACCTGAGTCTGCCAAGGACTAGCAGGTTGCTA 11880 ACCACCCTGTGTCTCAGTTTTCCTACCTGTAAAATGAAGATATTAACAGTAACTGCCTTC 11940 ATAGATAGAAGATAGATAGATTAGATAGATAGATAGATAGATAGATAGATAGATAGATAG 12000 ATAGATAGATAGGAAGTACTTAGAACAGGGTCTGACACAGGAAATGCTGTCCAAGTGTGC 12060 ACCAGGAGATAGTATCTGAGAAGGCTCAGTCTGGCACCATGTGGGTTGGGTGGGAACCTG 12120 GAGGCTGGAGAATGGGCTGAAGATGGCCAGTGGTGTGTGGAAGAGTCTGAGATGCAGGGA 12180 TGAGGAAGAGAAAGGAGATAAGGATGACCTCCAGGTCTCTGGCTATGGTGATTGGGTGCA 12240 GGCAGTGGCAGTCACTGGACTCAGACCCTGAAGCAAGGCAGCAGCTCATCGGAGTGTGAG 12300 CAGGCTCTGAGACATTTAGGTCTGGCCGTGCCTCATGTGTTGAATGTTATGGGAGATGGA 12360 GGTGGCGAGGAGCATGAGAATCATGAGCATCACTGCCCCTAGAGTATGTGCAAGGCACTG 12420 GACTTGCAGCAGATTGTGAGCTCTGCTGTGGACCCCAATCTGCACTGGGAGCTTTGGCAG 12480 GGTAAAGGGGAAGAAGAGCAAAAGCACAAGAATTCAGTTACGGCTTCTAATCCTGTCTGC 12540 TTTCTAGTACAGGCATACAGTCATCACTCAAGAAATGTTTATGTTCATTCACACTTTGGG 12600 CCAGACACTGTTCTAGACATCGAGGATACAGCTGCAAGTGAAACAGATACAACAACCCCC 12660 GACTCATGAAGTGTGTGCTCTAGCTGGGAGTGGGCAAGCAATGAGCCAAGTAAATTATTA 12720 AAAAAACAAATTATATAGCATTTGCAGCTTCAGATAGGGTGTTCACCAAGGAAGATCTCA 12780 CTAGAAAGCTGATATTTGAGCAAAGGCTTAAATTGCTGAAGGAGCAAGCCATGCGGCCAT 12840 TTTGGAGAAGGGAGCTCCATCCTGCAGCGGGACTGTGCTTGCCATGTTCAGGGGACAAGT 12900 GGGCCAGTGTGGCTGCGGGGAGAGAGTGAGAAAAAAAGTGGTCTCAGATGAGGTCAGAGA 12960 GCTAAAGTGGGAAGGTGAGATGAAAGGAGGCTACCGCAGTGGTCCAGGCTGGAGCTGATG 13020 GTGGGTGGACTAGAGTGGTAATGGTGAAGGCAGCAGGAAGTTGTTGGTGTTTGGATGGAT 13080 GAATGGACTAATGGATGGATGAATAATAGATAGATGGATTGTTGAGAGAGACAGAGAAGA 13140 GAAAAGCCTTGCCCCCAAAAGCTCACAGACTACTTGGAGAGAGAAGAAAGCTACCTGGAG 13200 GGAGAACCAGATGCATGAAGCAGTGCAGATGTGGTGCCTAATGAGTGTGTAGTCTGGAAG 13260 GGCAGCAAAAGTCGAGTGGAGTGAGAGGTTCCTGTGTCCTGGAGCACTGAGTAGAGACTC 13320 CCTCATGGGGGTGAATCTTAAAGGATAAAGGGGCCTCTATAATGAAAAGGAGGAGGATGG 13380 GATTTCTGGTAGAGGAAATTGCTTGAGCAAAACCTCCAAGGTTGGAATGACTATGGTGTG 13440 TTCAGGGATGTTAGCAGACCCAGATGGGTGGAGCGTTGAGTGTGTGTGTGTAGGAAGGAA 13500 GAGGGGAGGTGGCTGGATGAGCACAGTGAGACCTGATTTGATTGAGAGCCTTGAACGCCA 13560 CGCTGAATAATGGAGGCAATGGGACGCCATAGAGGGCTTTTGAGTAGACATATATCAGTG 13620 TAGAAGGGTGAATTTCAGATTTTTAGACAGAATAGAGTAAGGAGAGGAGCTCTTAGAAAT 13680 CATCTAGTCCAGGGCTTGTGGCAGAGCCCTGAGGTTTTAAGAAGGCATGTCAGGGGCTAC 13740 CATGACAGGCACGGAGAGGCTGAGTGAATTGGGGTTCTTGCCACAATTCCCTTGCCTGAG 13800 ATTCAACAAGAGCAGCTGTATTACAATCTGTGCAAAATGTCATTAGGAGAAACTAGTTAG 13860 TAGCTGGGCGTGGTGGCATGCAACTGTTGTCCCAGCTACTCGGGAGGCTGAGGCCGGAGA 13920 ATCGCTTGAAGCTGGGAGGCGGAGGTTGCAGTGAGCAGAGACTGTGCCACTGCACTCCAG 13980 CCTGGATGACAGAGCAAGACTCTGTTTCAAAAAAAAAAAAAAAAAAAACTAGTCAGGACT 14040 CTTTCAGATACAAGTAATAGAAACCAACTCAAACTGGCCTAATTAAAAGGATTTTTTTCC 14100 TTATAGCTAAAAAGCTCATGGATATCAGCTTCAGGAACACTTGGATCCAGGTGTTCAGCT 14160 GATGCTGGAAAGAATCTATGACTCCCCAACTCTCAGCCCTGCCAGGAAGGCTTTCCCCTT 14220 GTAGGACTCCGACTATCCGCCTTGTAGTATCTGATCCAGCAACACCAGTAAAATGAGGGC 14280 TTCTCTTTTCCCAGAGTCTTAACAAAAATCATGGAATTGAGTGTTATGGACTCATGGATT 14340 CATGGTAACCCAAACCAATCACCGGGCCAGAGGGGACAGAGTACCCTCACTGGTTGGCCT 14400 GGGTTACACACCTACTCCAGAGCTATATTTGGAAGCCGCATTGACTGATTTATGACCAGA 14460 AGAAAGGGAAATGGATGAGGACACGTGAAATTGTGTGTGTATGTGTGTGTGTGTTTTCTT 14520 GCTGCCAAAAATTTTTCAAAAACTTGGAAAATCACAGATATATTCAATCTCTTCATTACA 14580 CAAATAAGGAGATGGAGGCACAAATGGGGATAGAGGGATTTGCCCAGGTTCTCCTAGGGC 14640 TTCAGTGAGAAAAGTTTTGATCCAGGGATTCTGAAGGGGGTGGTGAGAAGAGGGGTGTCA 14700 GAGGACCTGTCTTGGGTGGTGGGGACTATGTACCTGTGACATAGCTGCTCAGGGACTGGA 14760 TCAATGGGTGGATGACAAAATGGACAAATAAACAAGGACATCTTCCCACTAATGCCAGAT 14820 GCTTGTGTGTTCTGCTTTCCAGAGAGTGCCTACTTGAACTTGAGCTCTGAGCAGAACCTC 14880 ATCCAGGAGGTGACCGTGGGGGAGGGGCTCAACCTCAAAGTCATGGTGGAGGCCTACCCA 14940 GGCCTGCAAGGTTTTAACTGGACCTACCTGGGACCCTTTTCTGACCACCAGCCTGAGCCC 15000 AAGCTTGCTAATGCTACCACCAAGGACACATACAGGTACCACTTATCAGCTCCCGTCTAC 15060 ACAGCCCGACAACCAGATGGGGTATGCTTCAGCAAGCATCAGGACGCTTGGCTCATGTCC 15120 CAACCTTGGTGTATGACCTTGAGCAAGTCCCTGCCCCTTTCTGGGCTTCGCTTTCCCTGA 15180 CTTCATGGAATCCCAATATTGGTCATCTGTGTTTGAGATCTAGATGAAATTGACCTACCT 15240 CTCCATCCCACATCCTTGGGATAGTCAATGCCCCACCCAAGGATTCTACCATTTCTTGGG 15300 AGTGTGCATTCTCATTGGTCCCTCAAGAACCCTCAGCCTCATTCATTTTCCTCTCTTGGG 15360 GCCAATCCAAATGCAGAAAACAGCCCCACTCATAGACACACTCCTGATAATGACTGCACA 15420 AGTTATCTGCTACATACAAAAGCTTGGAGGGAGGGGAAGAGGGAATTAAGATCACACAAT 15480 CACAGATACATGAAATGTTCTTTAAAGGATTGTGATCACCCAGCCCCAAGAATTTCTCAC 15540 TGGCTGCTCTTCTCTGTAAGCTCAAAACTCTTCCCATGAAGTGCAATCTATAATAACTCC 15600 ACACCCCTCTTCTTCCGTCTCTCCACTCCCACAATCCTGTGTATTCCACACACATTTTAG 15660 AAATCTTTTTCCTGTCTGCTTGTGAACTGTGTTCTTGGGGTCTTGCTTTCTCATCCAAAG 15720 TGGCTTAAGCAGGTAGGTTCTAAATAAGAAAGCTTTGTGCCTAAGAGGAACACTCATACC 15780 AGGTATATCAGGTATTAACTCAGGTATTAAAATAGTTCCTTCTTTTCTTTCTTTTTATTA 15840 TTTTTTTTAGATGGAGTTTTGCTCTTGTTGCTGGAGTGCAATGGCACAATCTCGGCTCAC 15900 TGCAAACTCGGCCTCCCGGGTTCAAGTGATTCTCCTGCCTCAGCCTCCCGAGTAGCTGGG 15960 ATTACAGATGCCCACCACCACACCCAGCTAATTTTTGTATTTTTAGTAGAGACAGAGTTT 16020 CACCATGTTGGCCAGGCTGGTCTCGAACTCCTGACCTCAGGTGATCTGCCTGCCTCGGCC 16080 TCCCAAGGTGCTAGGATTACAGGTGTGAGCCATCGTGCCTGGCCTGAAATAATCATTCAT 16140 ACCCTGCCCTTTCAGAGGGAGACAGTACAGCTTAAGGGCAGCGAATACGTGGTGTGCATG 16200 CCACACTCACTCTCATTCTTGTTTCTGCAACTCTGTTCTGCAGAGTGTAGATGCGGCCTC 16260 AGAGTCCTCCTCAACACAGGTCCCAGGCAGTATTTCCAGCATAGTTGGCTCATGAGAGAT 16320 CTGTTTGTCATCCCTGTGTGGATCCCTTAGACAACTTCAAAACTCTTTGGGATTCTCGTT 16380 CTAGCTCTGGAAGCCCAAACCTCATTGATTCCCACAATCTTGCTTGTCAATTGTCAGAAG 16440 CAACAAGGATGTTTTCTTGTCCTCATCTTCCTCCTCTCAGTTCCCTTCTGGTCCTTTCTG 16500 GCCAGGTCTCTGTCTTCCTCTCATTTAAAGCAGAAGTTCTGAATCTGGAATGTGTAGGCC 16560 CTTTGGAGGGGGCTGGTCCATGGATCGGTTTAATGGGTCCATAAGCCACAGAGACATTGA 16620 GGAAAGGAACACGAGATCCCCTAAAACACAGTAGTCTGGGCCCATTCAGCACAAGGCAGA 16680 CAAGCCTGGACACCAAACAGCCACAGAATTTTAGTTCATGTGATGGGTTGTTCATAATGG 16740 TGACTTTCAATTATCCAAAAAAGTCAAATTATTTTTAGTTAAAGGGGTTAGTTATCTCAA 16800 GAAGTGACCTGGGCAGAGGCCTTGTATATGCCCAGGGTCTGGCTGGATGAGACTGCTCTC 16860 TGAATACCATAGATTTTAGTCTAGTAGTAGCTGCAGACATTTCCCAAGCAAGAACTGGCC 16920 ATTTGCTATAATTTTTAAAATTTTATTTATTTTGACAGTGAACTGGGGGACTTTTTAAAA 16980 AATGTATTTATTACCTAAAACAACACATGTTCATTATGGACAAATTGTAAAATAGAGATT 17040 AAAGAAAGAATAAAACAAAAAATTTCCCAGAATCAGCCAAAGATGATTTTTATTGTTAGT 17100 TTTTGCTCCAGGGCCTTTTCTGTAATAAAGGGTACCATTGAATTGAGTGCCCACAAAGAT 17160 TCAACTTCTGTGTCAAGCACCCTAAAAAGGTCCTTTAATCCTCAAGCCAAGCCTGTGAAT 17220 TAATAACCATCGATATCACTCTCACAGCAAAGGAAGTGAGGGATCAGAGAGGTTAAGTAC 17280 TTGTCTAAGATCACACAGCCAAGAAACAGCAGCACCAGGACTTGAACCCCAGTCTCTGCA 17340 GCAACATGGCTCAGAACCCAGGGCCCTACATCCTGCCTCTTGTCTCTTTCTCAGTCCCTC 17400 TTGGCAAGGTTGGCACTTCAGGGATTTGTAGCAGGGATTGCAGCTTTCATGAAAGCTTAG 17460 TCCAGTGACAGTGGTCAACGTAGGCGACCTGTGATAGGCCTCCCAGCACCTTGAAGACAT 17520 CACCTCTATTAAACCTCGGGAAAAAAACACTTTCAGATAAGAAAACCAACTAAGGAAATG 17580 GGATTGGTGGTTTTTGCATGTCTCAATGGCACCCTGTCTGAGTATCTGGCTTACCCAAGG 17640 CCGTTGGGCCCTGAATATTTTACCAAAAATAAAATAAACCCCTTTAAGGCTGTTATCTGA 17700 CTGCAATCCTGGCAGGGGCCATACTAGGCTGGGGCTCACCAACACCACCTGATTCTCTCC 17760 TGCAGGCACACCTTCACCCTCTCTCTGCCCCGCCTGAAGCCCTCTGAGGCTGGCCGCTAC 17820 TCCTTCCTGGCCAGAAACCCAGGAGGCTGGAGAGCTCTGACGTTTGAGCTCACCCTTCGA 17880 TGTGAGTGCTGGGGCCGAGCGCCACCTGGGGCGGAGGCCCTGGGACTGCCTGGAGGGATG 17940 GGGTTGACTGGGGCAGGGCACAGGGAAGTAGGTACTGGGAGATTGGGAGGTGGCGGGGAA 18000 AGTGTGACTTGGGGCCTCCTCCTTTCTTCCTCAGACCCCCCAGAGGTAAGCGTCATATGG 18060 ACATTCATCAACGGCTCTGGCACCCTTTTGTGTGCTGCCTCTGGGTACCCCCAGCCCAAC 18120 GTGACATGGCTGCAGTGCAGTGGCCACACTGATAGGTAAGTGGGCTCCACTCACCTCCCT 18180 CACCTGGGCTCAGGGGCTGGGCACCCTGTGAGTGGGAGGGACATGCTGGCGCTGGGAACC 18240 CTGAAGCTCTGAGCCACATTCTGCTTTTGCCAGGTGTGATGAGGCCCAAGTGCTGCAGGT 18300 CTGGGATGACCCATACCCTGAGGTCCTGAGCCAGGAGCCCTTCCACAAGGTGACGGTGCA 18360 GAGCCTGCTGACTGTTGAGACCTTAGAGCACAACCAAACCTACGAGTGCAGGGCCCACAA 18420 CAGCGTGGGGAGTGGCTCCTGGGCCTTCATACCCATCTCTGCAGGTGAGAGGGAGCCTTC 18480 GCACCCGCACCGCCCCCCCGCCCGCCCCCCGCCCCTGCTCCTTTAGGCGGCTCCTCCCCC 18540 ACCCCCCACCGAGGGAGCTGGGGTTGGCTCCACCTTTGGAGCAGATCCTAGCAGTACCAA 18600 GGTCCACCTCTCTGGGCCAGTCCAAGCCCCTCCTGCCTGGCAGGTCCCCCGAAGCAGTAG 18660 GACGGGGTAGTCTCTGAGAAAGCAGAGAGAAAGCAGCCTGAAGAAACTGGCCCCCACTCT 18720 TGTCCCTGCACTCTAACTCATGCATCTATTCACAAGTATGTGCAGGCATTATGCACCGTG 18780 TGCCAGGGACGTGCCCTATGCAGGGAAGCAGTGCCTCCCCAGAGCTCAGAGGCTGATGAG 18840 GGAGGCAGGCAATGAGCAAGGAAACAGTCCATCTCCAGCTCGGGGCCAGCTAAGGACGGC 18900 CTTCTCCAACTCTCCCCTCTTGCTCCAGACACAGTCTATCCATTTGAGGTTGCTGTGCAA 18960 GAGGCTGCCCCGGGGGATGATGCCCGGCCCTGTGCACAACACAGGCTGCCTCTCTGCTTT 19020 ACACAAAGGCTCCTTACCAGCTAGTTCTGTGATTCTCAGAGGCCCACAGCATCCTCAGGC 19080 TTTTGACAACCAGGCTCTGGCACCCACTGTGTGCCAGACCCTGGCATCTGCCTGGCTCAG 19140 GGGTGGTCACTCACGTCCCCAGCTGCTGGCCTTGGAGCAACTGCTACCAGGGTCCAGCTG 19200 CAAGCAGGAGCCTGCGGCCGCGCTGGGCCTCACTGCTGGAGGTTGTATATTATAATAAAG 19260 CCAACATTTTGTTGAAGGCTTCTGCTGCGCCAGGCACTGTGTTAAGCTCTTTGTGGGGAT 19320 TATCTCGATTAACTCCTACAAACCTAGGAAATAAATAGAATTTTCCCTAGGCTCAATGTC 19380 ACACAGCTCCCAAGTGGCACAGGTGAAACTTGACTGCAGATCTAAGTTACTGATCTGAGC 19440 AAGGAAGTGGAAATTATGTTCTCCAAAACATCGCTAGAACTAGTAGTATAGATTCTGGGA 19500 AGAGGAGACTCAGGGGCCACAAGCCTGGCTTGCTAGACCCTCAGAAGGGCTGTATGATTC 19560 CAAAGGCATGTGGAGAAGCTGCAGGGGAAATGCAGGAGAGGAAGGTTGCAGTGTGACCTC 19620 CAGAAGGCCTTTCTGAACGAGCTTCCTGGAGGTGTAGTGCATGCAAGCCATGGCTGGGCA 19680 CCAGGCCAGGCCGCTGCAGAGAGGTTTCTTGCACTGGCAGAGGGTGAGACTGCATGACCC 19740 CAGAGGCTCCCTACCCCCAGCCACAGGAGGCTGTGACTCTGGACAGGGTTTGGGGCTGGG 19800 CATGAGCAGAGCTGAAGAGGCCGTCCTCTCTGCCTTTCTCGGGGAGGGTGTGCAGGAGAG 19860 GCTCCAGAGGCTTCCAGTGGAGGATGCTTCATTCAGTCAACAAGCATTTATTGAGCACCC 19920 ACTGTGTTCCAGGCAGTGTGCAGGCCTGACCTCAGGGGGCTCGGAGGCACCCCTGCCTGC 19980 TCACTGCTTTGCTTCATGCCTTCCAGGAGCCCACACGCATCCCCCGGATGAGTTCCTCTT 20040 CACACCAGTGGTGGTCGCCTGCATGTCCATCATGGCCTTGCTGCTGCTGCTGCTCCTGCT 20100 GCTATTGTACAAGTATAAGCAGGTGAGCCGGAGCGGAGTGGGGCTGCCAGGTGCCTGAGT 20160 GAGCCAGATTTGGATGGTACCCCCAGGCTGCATGGATTCACCCTTCCTCCTCCTCAGTCA 20220 GTCCATCAGCTAACAGCTCTTTAGTGGGTGCCTACTGTATGCCAACATGAGCCAGCTGCT 20280 GGGTGGCCTCTGAGGCTCTGCCCTAATAGCGTTTACTGTCTAGTGCGAGAGACAGGTGCT 20340 AATCAAATAGCCATTAAAGCAAGGGCACACCTGTAATCCCAGCTACTTGGGAGGTTGAGG 20400 CAGGGGGATTGCTTGAGGCCAGGAGTTAGGGACCAGCCTGGGTGATACAGCCAGATCCCA 20460 GCTCAAAAAACAAACAAAAAGCCGTGAAAGCAAGAGCATGGATTATAGAGTGAGAGGCTA 20520 TGAGGAGAGGAATGGCATTCTGAGGCAGCGCAGCCCTGGGATCCTGTCTCAGCCCAGGGG 20580 TGTCCTGGCACCCAGCACGGGGCAGAGGAAATGGATATACAAGCGTGGTGTCCCCTGGGC 20640 CAGGCCTGAGCCCTGCCCTAAGAAGCACATGGTCTAGTGAAGACGAGGGCCTGTGACCAT 20700 CATCCTCTTCATTATTTCATGTTACTGTCCTATTAGCCAAAGCCACAATTTAGTGCATGT 20760 TGCGTATAGTGTGCTTCCTGTGTCTGCTCAGTATATGACAGTGATTTGAGGGGCATTTTT 20820 CTATAGCATGTTACCTACATCATCTCATTTAATGCCCTCAGCAACCACTGTATGCAGCTA 20880 GCATTAGTCTATTTTACAGAGTTGTAAACTGAGGTTCTGAGAGGTTGGGACAGTTGCCCT 20940 TGTCTACAGCTGGTCAAAGGCAGAGTCTGGTTTTTAACCCTGAAGGAGGACTCACTCCAA 21000 AGCATGTCCCAATCATTATGTGAAACATTGACTCATCTTATTTTACCCTCACAAGAAGCT 21060 GGAGGCAGGAAGTATACTAGTCAGTATCTTACCCATCAGGAAGCTGAGGCTCAGCAAGGT 21120 TAAAAAAAAAACCCCAAGGGGCTGAGGGATAGGGTTGGCACTGGGCCCCAGGGGCTTCTG 21180 TCCCTAGAGCCCATGGCCTCCACTGCCTGCCTGCCCACACAAAGACCATGTGCAATGTGA 21240 TCAGAAGCTGAGAGGACCAGGCCAGAGGGCTGTGGGAGTTCAGAGGTGGACGGACTTTTC 21300 AGGCTGGTGGGTAAGGGAGACTGCCTGGAGGAGGTGGCTTGGCATTGGTGGGACGGGCTT 21360 TGGAGGATGAGGATGCAGCAGGGGAGATGACACTAAGGGAAAGGGTATCTCTGGGGGAGA 21420 GGGCAGAGTGTGCAGAGGTGCAGGTGAGGGAAGGACCAGGGTGGGGCTGGGGGTCTGAAG 21480 GGTTGGACCCCACCCTGTCGGTCCAAGGCCATCAGTGGGTTTGAACAAGGGAGTGGTGTG 21540 ATCAAGGACTGAATGACCCATCTTGTGTCCCCTTGGCTACCTTTTCTTCCCCACACCCCT 21600 TGGGGCTTTTGTGAGAAGAGGGCTTGAAGTGGGCAGGGTGGGAAGGATGTTGGGGGAGCC 21660 CCAGGGGCACATGGATCGGGATCTCTACTCCTGCCAGCACTCAGCATGAGAAGGCTGCTC 21720 TGAGGGCAGCCCCGGTCAATACCTCCGGATCTAGGTCCAGCTCTGACACTGTTTTGCCAT 21780 GTAACCTCAGCTGACTCGCTGTCCTCTCTGGGCCTTAGTTTCCCCTCTTATACCATGGGT 21840 CTGGGTGTTCTCTAACAGCCCCTCCTCCTCTGACATGCCAAGAGCCCACTGGTGGTCTAG 21900 TTTAAGCACCAGAAACTTGGACTTCAGTGAATCTGGGTCCAAATCCTGCCTCTGCCAAGC 21960 TCTGGCTATGGGGTGATGAGAAAGTTGGTGTGTCTGAGTCTCTTCTCCATTTGTAAAATG 22020 GGATCATTAACAGCCTGTTGTGAGGGATTCCGTACCACAACGCACATAGAGGACTGAGCG 22080 GGGTGCTGGACGAGACAGTCTCTGTGATGGGAGCTGCACACTCTTGTCCCAGGAGGAAGT 22140 TCGTTGGGGAACCAGAGTTAGCTCATGCCTCTTGGGATGGTGGAAGGAGGGGGAGGTCTG 22200 AGGTCGGGCATCATCTCCTTGACTACACACCCAAAGCGGTTGTTTGGCCCAGCCCACCCA 22260 CCTCCAGGGACAGGACCTTACTCACTCTCGGGGCCACCCGTTCCTTCTCTGAGCAGCTCC 22320 AATGTTTGCAAAGTTCTTCCTTACATGGAACTGAAAACTGCCTCGCAGTGCCCACAGAGC 22380 TGCCAGGACAGTCATGCAGAGATTCCAGAGAAGGGCCTAGGGCCCCCTGCGGCCCTTTCT 22440 GCCTTGGGCTGGCCAGCCCCCTTGGCTGTGGTTTAGGAACTCTGTATCCCCTCTCCACGG 22500 GACCATTTTTGGAACATGTCACCTCCACACTTCCTGTCCAGGAAATTCAGCTGCCCCTGG 22560 AGCCCATGCAAGGCTGCGAGAAGACTTGCAGCTACCCTCCTCCCCTACACCCATTCACAG 22620 ACCCTTTAGCTCCAGGCCGAGGTGTCCACCCATGGGAGCGGAGGGGGCAGGATGGTCATG 22680 CCCGTGCTAAGTGCCTGCCCTCCCATCCTCCTCTGCCTTGCCCCATGAGGTTCGGAGCCT 22740 TGCCCCTTCACTGGGGACTCAGCCCAGCCTCTCCTCATTGCCCAGGCCTGGGGAAAGAAG 22800 TGGCCTGTCTGTGGGGAGTGTTTGTTCTGCCTCAGGGCTGAATCATCACCTTTCTGTCCC 22860 CCAGAGTGACCACAAGGGGGGCCGTGGGGGAAGAGAAAAGGGCAGGAGTCAGCAGGCTCC 22920 CCTGGAGGAGGAGGCGCACAGGGAAATGGCTGAGGCAGCAGGGAAGGGAGGGTCCAGGGA 22980 GGCTGCTGGAAAGACTACGATTCTGGGGGCTGGAACTGAGCTCTGAGGAGCAACAGGAGG 23040 GTCCCCAAAGATTCCACTGGGAATTGTTCAGATCTCCACCTTCCTGTGAGAACATCCACT 23100 CACCCAGAACCAGCAGGCCTAGATGGGGAGGGGACCGGGACTTTGTCTCCATGCCCCCTT 23160 TGGTGGGGAGGATGGGAGGAAGGGAAGAAGTCAGGGGGTGGGCCTGGGGCTTAGGCCCAT 23220 TGCAAGGAATGAATGGGGTGATGTGCTTCAAGCATCTAGCCCAGCGCCCCACTCCCAGGA 23280 AGAGCTCAGGAAGAACCCGCTGCCATCATGACAATTACGTCCACCCTTCTCAGGGAGCCT 23340 CGCCCATCCCCACCTCTTGATCTCTCACTCATAGTTCTTTGGAAGAGAGGCTGCCTCTGG 23400 GTAGACGCCCATGAGCCCTTTCCAGGGATGGCACAGGTGCCCTGGGAGGTTTACATGCCC 23460 AGCAGGGGCAGGGGAGGGTTCCTGAGGCAGGCAGAAGGCAGCTTGGTCCGCTTCCAGAAA 23520 TTAGGAGCCTAGGATTCAGAAATCTGAGAATCCAGCCAAACCTCCATCCTCCTTGATCCC 23580 CTCCCTTTCAACAGTGCCCCCTGCCCAGCTGGGGGCAGGGAGGGGCTGACTCAGCCCAGC 23640 TGCAGAGGGACAGAGGAACAAGAAGTGGTAAGAAAAAACAGTCTTAGCCACAGAGGCTCC 23700 TAGAGATGGAAGTGGCCAGGAGAGGCTGAAGAATCCCCTCCTCGCCTTGTTGCTGTCTTT 23760 TGGGCTGGGAAGGCACCCACGGGCAGGATTTGGATCCTCAGAGGCTTGGGAAGCTCTTCT 23820 CCCTGGGTCCCGTTTCAGACTCTCTCCCAAGCTATAACGCAGAGGCTCTGAAGTTCACCT 23880 GCAGTCCGCCCTTCCAAATCAGAGCCTGGAAGTTAGTTCCTTCTCATTTCTAATTGCAGT 23940 CTTTTCTCTCTAACTACCAGCTAGAAGTTCTTCCTGATGGTTAGCTGGAAGCTTTCTCCC 24000 TGTCTCTCTCTTTAAAAATGTCCACATTTTATTTTTGATTCAGGGGATAGACGTACAGGT 24060 TTGTTGCATGCGTATGTTTCGTGATGCTGAGCTTTGGAATATGGATCCCATCACCTGCTA 24120 CTGAGCATAGCTCCCATAGTTTTTCAACCCTCGCCCGCTTCCACCCTCCCTGCTCTAGTA 24180 GCCCCCAGTGTCTGTTGGTGCCATCTTTATGCCCATGCACACTCAATATTTAGCTCCCAC 24240 TTATAAGTGAGAACATGCGGTATGTAGGTTTTCTGTTTCGGTGTTAATTTGCTTAGGATA 24300 ATGGCCTTCAGCTGCACCACGTTGCTGCAAAGGACATGACTGGAATCTTCTCTCTCAACC 24360 AGGACTTGCAGCTAAAGGCCAGCCTCCTCCCTAGCACCGGTCCACACTTCCTTTAAGTTT 24420 CTAGCTCGGGTGCCCAGGGAAGGAGCCCAGCTGCAGGCACAGCCAAGCTTGTCCCATCCC 24480 CAAGGCCTGGCCGGAAAGAGTTGCTCTGCTGACCCAGGGCCTCAGTGTCCTCCACCGCCC 24540 CAGCCCAGCTTCCACTTTCCCCCTCAACTTGGTCTTCCATCAGCATTTCTTATGGGCAAC 24600 CCTTAGCATGGTACTCCCCCTCAGCAGCTGACCCCTGGGCAAGAAACAGGGGCAGCCATT 24660 CCTCCTCCCCACATCCCAGGGCTTGCCTCCCCTGGCTGGGTGGTAACAGCATGGAGAGCC 24720 TAAGGAAGGAAATCAGGTCTTTCCAAAGGTGCTGGTCCTCCAGAATCTATCTAGTGGGCA 24780 GCGTCTCTCTTTCTCTCTCAAAAAGGTAAAGTCAAGGCTGGGTGCGATGGCTCACGCCTA 24840 TAATCCCAGCACTTTGAGAGGCCAAGGCAGAAGGATTGCTTGAGCCCAGGAGTTTGAGCC 24900 TAGTGAGCTATGATCGTGCCACTGCACTCCGGCATGAGTGAAGGAGCAAGACTCTGTCTC 24960 AAAAAAAAAAAGTCAGATGGCGACTCACCTGTGTCAAACTCTCAGGGTCTCTCACTGCCC 25020 GGCCAGGCATGGTAGCTCATGCCTGTAATCCCAGCACTTTGAGAGACCGAGGCAGGCAAA 25080 CTGCTTGAGCTCACGAGTTCAAGACCAGCCTAGGCTGCGACAAAGCCCCGTCTCTACAAA 25140 AATTAGCCAGGTGTGGTGCCACATGCTTGTAGTCCCGGCTGCTTGGGAGACTGAGGTGGG 25200 AGGATTGCTTGAACCTCGGGGGTCGAGGCTGTAGTGAGCCAAGACTGCCCCCACTGCATG 25260 CCAGTCTGGGGGACAGAGATCCTGTCTTGGAAAAAAAAAAATCCCAAAAGGGAACCCACT 25320 CACCTTATCATAGCCCTCAAGGCCTTCCTGTTTCTGGAATCTGCCCCCCACTTCCCTCAA 25380 GCCATGATGGCTGCCTTCCTATAGCTCAAACTTGCCAGGATCATTCCCATGTCAAGCATA 25440 CAGCATTTCCATGCACTGTTCCTGGAAAATTCTTCCTCTGATGGTCACATGGTGGGCTCT 25500 TTAGGGGCCTTCCCTGACTTATCTTACTTTATTTTCTTCATAGCACCACTTGAGAATCTC 25560 CTAGATACATGTTTATTTGCGTTTAATGCCTCTCTCAGCCACTAGAATGCAAACTCCATG 25620 GAGGGGCAGGGACTTTGTCCTGTTCAACTCTGAATCAGCGGTGCCTGACACAAATAGATG 25680 TTCAAGAAAGTATGTGGATGGGCTACTATTATTCAGCCTTAAAAAGGAAGGGAATTCTGA 25740 CCTGTGCTGCAGCATGAATGAACCTTGAAGACATTATGCTGGGTGAAATAAGGCAATCTC 25800 AATAGACACATGCTGTGTGAGTCCACTGAGGTGCAGTGCCTAGAGCAGTGCAATTCACAG 25860 AGACAGCAGAATCATGGTTGCCAGGGGCTGGAGGAGGGAAAGGGGAGTTGCTTTTTAACA 25920 GGAACAGAATTTCAGTTTTGCAAGATGAAAAGAGCTCTGGAAACTGGTTGCACAAGGTAG 25980 AATGTAATTTACTTAATACTACTGAACCATACACTTAAAAATGGTTGAAATGGTAAATTT 26040 CATGTATGTTTTATCACAATTAAAATATATATATATATTTGGATGGGAGGTTGGGTGGGT 26100 GGATGGATGGGTAGATGGATGGACAGATGAACGGATGGATAAGATCTCAAGTTCCACCCT 26160 CCCTCCTGGCTCAGGAATTACCAGATTATCAGAGATATCAGGGCCCTCAGAGGTTGTCTT 26220 GTCCAAGGTCTTCAATACACAAATAGTGAAACAGGCTTGGAGAAGGGAAGGTCACACAAC 26280 AAGGCAGAGTCAAGCAGGAACATGCTCTCAGTGCTATGTTCATGAGACGACCTCTCTCAG 26340 CCCAGAGCAGGCCTTGCCCTGCCTTCTCCCACTGGGCGCCTTGGGACTGCCCACACCCCT 26400 GCTCTTGGGGGTCAGAAACAAGGTCCAGGAACTGCCTGCCAGCCCCGACTGCCACGTGCT 26460 CCCTTCCTCTTCTGCAGAAGCCCAAGTACCAGGTCCGCTGGAAGATCATCGAGAGCTATG 26520 AGGGCAACAGTTATACTTTCATCGACCCCACGCAGCTGCCTTACAACGAGAAGTGGGAGT 26580 TCCCCCGGAACAACCTGCAGTTTGGTGAGATGGCAGCTCATCACTCCACAGCTTCCTATC 26640 ACAGGGCCTGTGGGGGTTGCAGGGAGCCCATGGGCCCTTGGACAGAGGCCCTTTGGTGCC 26700 CAGGGACTTAAGGGACCTGTGTGCGTGGCAGGTAAGACCCTCGGAGCTGGAGCCTTTGGG 26760 AAGGTGGTGGAGGCCACGGCCTTTGGTCTGGGCAAGGAGGATGCTGTCCTGAAGGTGGCT 26820 GTGAAGATGCTGAAGTGTGAGTGAGGGGAGGGGATGAGGGAAGGGATGGGGGTGGTAGAT 26880 GCTGGGGGTGGGCTGGCCCTGGTGTCACAAGAGGCATCACACACATTTCAACCTGTTGAA 26940 GCCTGGGGGACAGAGCTCAGGGGTGAGGACTTGGGTTTTCTTGTGAGCTCCAGGCACCCT 27000 CTGACTCCCGGCTCCAAGAAGGTCTAGGTCACCCTTTAGTTGTGAAGGGGCTCCTGACTG 27060 AGCTCCAAAAAGTCTGGGGGTGCAGAAAGGCCACCTATGGCCATGGCCTGGCCACAGTTT 27120 GGCTTCCTGTCACCTGAAGACCAGCTCAGTGACAGGCTCATCCCTTCTCTCTCTCTCTCT 27180 GCCATCTGTGTGTCTGCATTTTTCCTTCTCCTTCTTTTGGCTTCTGGTCACTCCGGGTCT 27240 TGGGATATGCCCTGCTTTCTCCCCTGGGTCTCTGCATTTGGTCCCCATGTATCTGTGTGG 27300 TGCTCTCTGTCCTGCCCTCTCCCTGTCTTTGGGACTGTGGTTCTTCCTCCCAGCCACGGC 27360 CCATGCTGATGAGAAGGAGGCCCTCATGTCCGAGCTGAAGATCATGAGCCACCTGGGCCA 27420 GCACGAGAACATCGTCAACCTTCTGGGAGCCTGTACCCATGGAGGTAAGGGCCTTGGGGT 27480 TCCTGGGGCCAAGGTCTTGGGGCCTCTGGGGAATCTCAGGGCCCCAGGGCTACCTTGTTC 27540 CGTCTTCTCCTTCTCAGGATCCTACTGCTCCAAGTGTCAGGGGGATCCCGGTCACAGCAT 27600 CCCTTAAACTCCTGGGCCCATCTCCTGGAATAGTCAGGAGCTGCACGGGCAGCTTGAGGT 27660 ATAAAGAGAGACTGATAGGGAGCATCGGAGCCCTTGGAGGAGGAGATGAATGTGCAAGCT 27720 CCTAGGCCCTGCTTCCAGGGAGCCGGATCCTCTGGGTCTGGAGTGAAGCCCCCCGCCTAC 27780 CTCTTATGAAGCTTCCATTCAAGGATGCTTGGACACTCTCCCCAGGGCCCCCAAAGGTGC 27840 CCCGGGCTTTGCTGGGACTCCAAGTGCCCCACATCCTCTTCACTGATAGCAGCTCTGACC 27900 TACAGTGAGCCGCCATAGCTTTCCTTTGAAGAAATAATTCTTGGGCTACATTTTTTTTAA 27960 GGTTGTCTTTTTTTTTTCATTTTTTGTTTTTTTTTTCTTGAGACGGAGCCTCACTCTGTC 28020 ACCCAGGCTGGAGTGCAGTGGTGCGATCTCGGCTCACTGCAACCTCTGCCTCCCAGGTTC 28080 AAGCAATTCTCCTGCCTCAACCTCCTGAGTAGTTGGAACTACAGGCACATGCCACCATGC 28140 CCGGCTGATTTTTTTGTATTTTTGTAGAGATGGGGTTTCACCATGTTAGCCAGGATGGTC 28200 TCGATCTCCTGACCTCGTGATCCACCCACCTTGGCCTCCCAAAGTGCTGAGATTACAGGC 28260 ATGAGCCACCGTGCCCCGCCAAAGCCATCTGTTTTAAACAAATGGAACTACTGAGGCACA 28320 AGGAAACTTGCTCACAGAGCCGAGGTTAGAACTCAGCTATGCTGAGTCCAAGTCCAGTGG 28380 CCTCACTGCCCCCAGTCTCATGCTCCTGTTCATGGAGGGGAGCACTCAGCACCTCCCTCA 28440 CCCCACACCCTTGGCTGCTCTAGGCCCTGTACTGGTCATCACGGAGTACTGTTGCTATGG 28500 CGACCTGCTCAACTTTCTGCGAAGGAAGGCTGAGGCCATGCTGGGACCCAGCCTGAGCCC 28560 CGGCCAGGACCCCGAGGGAGGCGTCGACTATAAGAACATCCACCTCGAGAAGAAATATGT 28620 CCGCAGGTAGCCCCTGGCAAAGGACAAGAAAAAGGCCAGGTCTGGGAGGCAGGATCCGAG 28680 TCTGTCTTCAAAGCCAGCTCAGGGTTGGATGGCTCATGAATGGGTGGCTATGCAGCCCTC 28740 ACCTGCCACCTGTGTCATGGGAAGTAGCCACCACAGGTTTTATGGCCATCTCTTGTTTCT 28800 CTACTCCTTTTCCCCTTCATTCAACAAATATTTGAACACCTACCGTGTTCTGGGAGTGTG 28860 GAGGGCAAAGATGGGCAGCTCATAATCTGGTGGAGATATGCATCAATGAAATCACCACCC 28920 AGTGTGTGTAAAAGATCAACCAAGATCTGTGCCTGGAGCCCTAGTAAGAGATGGGCAGAT 28980 GTGGCCGGGTGCAGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGGCTGAGGCGGGCA 29040 GATCACCTGAGGATGGGAGTTCGAGACCAGCCTTACCAACAAGGTGAAACCCCGTCTCTA 29100 TTAAATATACAAAATTAGCCGGGCGTGGTGGCGCATGCCTATAATCCCAGCTACTCGGGA 29160 GGCTGAGGCGGGAGAATTGCTTGAACCCAGGAGGCAGAGGTTGCTGTGAGCTGAGATCAC 29220 ACCATTGCACTCCAGCCTGGGCAACAAGAATGAAACTCCGTCTCAAAAAAAAAGAGAGAT 29280 GGCTCTGTTGTCCTGTTGCTGTGATTCCTGGAAGCCATCCAGAACAGAGCCATCCAACAG 29340 ACAGAGCCACATGGGGAACCAAAGAGAGGAAGTGGGGAGATTCATGTCACACATGAGTCA 29400 GGGTTAGAGGTGGAGCCTGGACTAGAATCCTGCTCTCTTGACTTCCAGTCCAGGAGTCAC 29460 CCAAGCCACACTGCTGTCCTGGAGGTCTCTGTCTCAGGGGCTTGTGGGGTCAGGACAGGA 29520 TCAGAACAAGAAGGGTGTACACTGCGCCCTCATCCTAGATACTGTCAGCTGCCACGCCTG 29580 GGGAGGCAAAAGAGAAGGAGGCCATCTCTTCACCCAGGGCCTTAAAAATGGGGGCCTGGC 29640 AGCATCACTTCCTCTTCTGATTCCCTGACACTTCTATGAGGGTGGCACACACTAGGCCTC 29700 TGAAGATCAGATCAAAATGAGCACCAAAGGAAAGTATTAGCTTCCATCTTCAAATACGCA 29760 GATGGGGAAAGTATTCCCAGAGTGGGTAATTTCGAGGGCAAATGGCCTGTAAACCAACTC 29820 TGTCAAAGGATTCCAGGCTGTTAACGGAAGCATAGTTTCTACAAGGGAGCGGAAGGTTTT 29880 TTCGGTTTCTCCTTCTGGGAACACTAGAATATGGACATTGTCAAGGTACACATCTCTAGC 29940 GCAGAGGGGACAGGAGGGAGAGAGAAATCCTATCTGGCTGGAACGTTAGGAGCAGTAGTG 30000 CTTCAGTCTACAGTAGTGCTTCTCAAATTCTCTACCCCAAGTGTGCTCTCATAGGCATCT 30060 CTTGAGGACTGTTGGAAGTGCACCACCTCAGGCCCATCCACCCAGGCCTGCTGATTCAAA 30120 ATCTGCATTGCAGAGATTCCCGGGGTGATTTATCTGCACATGAGTTGCAGCGTAAGCAGC 30180 ACTGCTCTAGACCAGTGGGCCTCAGCTTAGGCTGTACTTTGTGATCACCTGGGGAGATTT 30240 AAATCTGTGAATGACTGTTTTGTCCCTAGAGTTTCTGAAGTATTAGTAATTAGCCTGATC 30300 CTAAAAGCTCCCGAAGTGATTTTAATGTGAAGCCAGGGGTGTGAGGCACTGTCCAGAGAA 30360 GAGAGGGCACAAGGGGCCCTAGAATATGCCCCAATTCTAGTAGGGCTGTTATGGGGAAGA 30420 GGACTCCAACTTCTCTGTGGCCCTTGAGGGTAGAGCAGGGGCTAGGAGGAAAATCTCAGG 30480 GGTAGATTGGCATTAGGAACAGTGAAGAACTTTCTCACAGGCAGAGCTGCCCAAAACCAG 30540 AATGGGTTGTAAGCTCCCTCACCGGGGACAGCCGAGCAGAGACCAATGCTCACTCAGATG 30600 GAGTGTGGCAGGAGGGTTTCTTATCAGAAAGGGAGGTTCCAGTTGACCATGGGGTGGTGG 30660 GTGGTCAAGGCCTGAGCTGAGCAGTGCAGTGATGATGACTGACCTCTGCCCCCCAACCCT 30720 CTCTCCTATGTAGGGACAGTGGCTTCTCCAGCCAGGGTGTGGACACCTATGTGGAGATGA 30780 GGCCTGTCTCCACTTCTTCAAATGACTCCTTCTCTGAGCAAGGTGAGGAGGTCCCAGGGC 30840 CAGGCCCCATTTGCTTGATAACAAGGGAAAAGGAGAAGGGGCTGCTGGGGTGAGGGGTGG 30900 GGAGTGTGGCAGGGCTGCCCTGACGCCTCTTCCCACCCTAGACCTGGACAAGGAGGATGG 30960 ACGGCCCCTGGAGCTCCGGGACCTGCTTCACTTCTCCAGCCAAGTAGCCCAGGGCATGGC 31020 CTTCCTCGCTTCCAAGAATGTGAGTAGGAACCTGGCCCTGGCTCATAGCCACCCAGGTCT 31080 GTGCTCCGGGGAGGCTGGATGAGTGACGATGGGGAGGAGGAAACGGGAGCCTGTGAGGGG 31140 GTAGGGGAGGAGACAGAGTATGAGAGAGTCATTTGGGCAGCAGCTGCAAGGATGAGTGGG 31200 AGAAAGCTGTGCCCAGGGCTGGAGCTCTGGGGCTGGGCACCTGTGTCCCCAGCGTGAAGA 31260 TGAGGAAGGGTACCAGGCTTTCTTCATTCGTTTTTACTAAATAGTGTATGAGAGACAACA 31320 GTTGTCTCTGCTCATAAAGCACGTGGTCTGGTGGGGATGATAACGGAAGCTTCCTCAGAA 31380 TTTTGGGGATATTAGATAACGTATAAAGTGCGCTCGGCCTAGGAAGAAGTGCCAGGGAAT 31440 GGGAGCTCTTGCCATCTTCCTTAGAACAGATTCGGGAGTCAGTGGTTTGATTGTTGGCTC 31500 TGCCACCTGCTCCGTGACTTTAAGCAACTATTTAAATTCTGTGCCTCAGTTTCTACACCT 31560 ATAAAAATGGGCATAACGATTGTTGAAAAGAAAAAGGGTTCAATGTGTGCAGAGTTTAGG 31620 GAAGGGCCTGGCAGATAGCAGCTGCTATGATCAGAAGTAACGGTAGGGTTTGGAGACTGC 31680 TCTCTGCACGGAAGCCCTTCGCTTCTGGGGCCTGAGCAGACCAGTCAGAGGACAAAGGGT 31740 GAGAAGGGCCATGGCTGCTCAGGGTAATGGGGGTTTCTAAGCATTAAATGATCAGATCAC 31800 GATACACATTCTCAGATCCTGGGCCCTGGTAGAAGGTATAGACAAGGGTTTGTGGTAAAG 31860 GACCAAAACTGTTGTTCACTCCAGCAGGGACTCCAAAGCCATGTGGGGCCCTCCCTGCCA 31920 TCCTCCTCACCTCAGGCTCAGGTAGGAGAAGGCCCAAGACTAACCCTGCAGTGCTTTCCC 31980 TCAGTGCATCCACCGGGACGTGGCAGCGCGTAACGTGCTGTTGACCAATGGTCATGTGGC 32040 CAAGATTGGGGACTTCGGGCTGGCTAGGGACATCATGAATGACTCCAACTACATTGTCAA 32100 GGGCAATGTAAGTGCTGGGAGGGCTTGGGTCAGGCTGGGGAGGGGGTGAAGAGTCGGGGC 32160 CCAAAATAACTGGGGACTGTCATCCCAGGCCCGCCTGCCTGTGAAGTGGATGGCCCCAGA 32220 GAGCATCTTTGACTGTGTCTACACGGTTCAGAGCGACGTCTGGTCCTATGGCATCCTCCT 32280 CTGGGAGATCTTCTCACTTGGTGAGCCACTGGGCCCACTCCAGGCAGAGCCTGGGGCTGG 32340 CTCCTCTGGTTGCCCCACTGGTGGACAAAGCTGTTTGGTGCCCAGGACACAGCGAGGGTT 32400 GGTGAGAGTGCAGGAATGGGCAAGGGCTCTCGAAACCCAGCATCGTGGCTCCTGCGGGAC 32460 TCGGCAGACCCTCTGCCCCTGACAGGCGCTCCTTTCTGGCTCTTCCCTCGTTTGTCTCTG 32520 CTCAGTTGCTGTTACCTGTTACCCTCCTTTGTCACTGTTTCCCTCCTTTGTCTGAAATCT 32580 ACAGACCCTTGAAGATGCAGCTCTCTACTACTAGGCTCTAGTAGAAAGAACTGCTATTTC 32640 CCGAGGACTAGGCACAAGGACTTGTACTCAGTTCTTAAATACGCTGCTCCTATACCCTCA 32700 TAACCACCTGACTGTCCACACTTTAACGATACACAGCTGAAGCTTTGGTCTGATTCCAAA 32760 GCCTGTGCAAGAATGTTTGGTGTGATAAGGCCTGGATAGAGGCTCACACCTTCCTAAAGC 32820 CTAAGCCTGCCACACACTGGCTGGCACACAGGAAGCACCGGGTAAGAGTAGCTGCTGTTG 32880 CAGATGTTGTCAAGTGGGACCCTTTAAACCCAGTCTAAGATGTGTGTGGGTGTGCGGGAA 32940 TGGGGAGAAGACAATGGGCATGGCCTCTTACCTGATCTTGGCCTTTGCAGGGCTGAATCC 33000 CTACCCTGGCATCCTGGTGAACAGCAAGTTCTATAAACTGGTGAAGGATGGATACCAAAT 33060 GGCCCAGCCTGCATTTGCCCCAAAGAATATGTAAGCGAAGGGATCCCAGGGAGGGAAAAG 33120 GACACCCCAGGCTTTCGCTGGAAAGGGATGGAAGGCCGTGTGGCCCTGATCTTTCCCTGT 33180 CCAAAATGTTCCAGGGTCAGACTTTATCTCTCCCATAGTGGACACAACAAGCCCCTTTTG 33240 AGTTCAAGCTATGGGGGATGTTCTCAGAGAAGCAGCTGTTCACTAGGGCTGGTCCTAACC 33300 GACCACTTTTCCTTTTTTTTTTTTTTTTTTTTTGAGACAGCATCTTGCTCTGTAGCCCGG 33360 GCTGGAGCGCAGTGATGTGTGCAATCATAGCTCACTGCAGCCTCAATCTTCAGGGCTCAA 33420 GCAATCCTTTGGCCTCAGCCTCCCAAACAGCTGGGACTACAGGTGTGCACCACCAAGCCC 33480 AGCTATTTTTAAAAAATTTTTTAGTAGAGATGGGATCTCACTATGTTGTCCAGGCTGGTC 33540 TGGAACTCCTGGCCTTATGCAATCCTCCTGCATCAACCTCCCAAAGTGTTGGGATTACAG 33600 GAATGAGCCACTGCACCTGTCCCTAAACAGACTTTTAAGAGATCGTTATTACAGTTACCC 33660 TGAGGATACCAAAATGGCCTCATCTGTCAGAATGAGGGTGATGAGAGTACCCTTCTGCAA 33720 GGGTTACTGTGAGGATTAAATGGTAAAGCATGCCAAGGACTTGGCATAGGTTTTATACTA 33780 AACTTACTTTGACTGGGTTTGGGGACCTCTGCTGGGTAGGTCTCTCTAGGGGTGTGTGTT 33840 AATGGCCCCTGGACCCTAGGGAGCTGCCCATGGGCATCCTCTGTCCTATCTCCCAGATAC 33900 AGCATCATGCAGGCCTGCTGGGCCTTGGAGCCCACCCACAGACCCACCTTCCAGCAGATC 33960 TGCTCCTTCCTTCAGGAGCAGGCCCAAGAGGACAGGAGAGAGCGGGTGAGTGGGGTGAGG 34020 CTTGGGGTGGGTGGCCGGTAAAGCACGTTGGGCTGGGCCTGATGGATCTGGACTGACAGT 34080 TTCTGGTCCCTCCCACCCTCAGGACTATACCAATCTGCCGAGCAGCAGCAGAAGCGGTGG 34140 CAGCGGCAGCAGCAGCAGTGAGCTGGAGGAGGAGAGCTCTAGTGAGCACCTGACCTGCTG 34200 CGAGCAAGGGGATATCGCCCAGCCCTTGCTGCAGCCCAACAACTATCAGTTCTGCTGAGG 34260 AGTTGACGACAGGGAGTACCACTCTCCCCTCCTCCAAACTTCAACTCCTCCATGGATGGG 34320 GCGACACGGGGAGAACATACAAACTCTGCCTTCGGTCATTTCACTCAACAGCTCGGCCCA 34380 GCTCTGAAACTTGGGAAGGTGAGGGATTCAGGGGAGGTCAGAGGATCCCACTTCCTGAGC 34440 ATGGGCCATCACTGCCAGTCAGGGGCTGGGGGCTGAGCCCTCACCCCCCGCCTCCCCTAC 34500 TGTTCTCATGGTGTTGGCCTCGTGTTTGCTATGCCAACTAGTAGAACCTTCTTTCCTAAT 34560 CCCCTTATCTTCATGGAAATGGACTGACTTTATGCCTATGAAGTCCCCAGGAGCTACACT 34620 GATACTGAGAAAACCAGGCTCTTTGGGGCTAGACAGACTGGCAGAGAGTGAGATCTCCCT 34680 CTCTGAGAGGAGCAGCAGATGCTCACAGACCACACTCAGCTCAGGCCCCTTGGAGCAGGA 34740 TGGCTCCTCTAAGAATCTCACAGGACCTCTTAGTCTCTGCCCTATACGCCGCCTTCACTC 34800 CACAGCCTCACCCCTCCCACCCCCATACTGGTACTGCTGTAATGAGCCAAGTGGCAGCTA 34860 AAAGTTGGGGGTGTTCTGCCCAGTCCCGTCATTCTGGGCTAGAAGGCAGGGGACCTTGGC 34920 ATGTGGCTGGCCACACCAAGCAGGAAGCACAAACTCCCCCAAGCTGACTCATCCTAACTA 34980 ACAGTCACGCCGTGGGATGTCTCTGTCCACATTAAACTAACAGCATTAATGCAGTCAGCC 35040 TCTGGTTCTTTGTGCCACATGAGTACCTGCAAATTCCCTGGAACGTCTTTCTTTCCTTCC 35100 (2) INFORMATION FOR SEQ ID NO:20: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 218 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20: ATTTATTATTTTTTGCAGAAAGAGCACTTCAAATAATTTACAGAACCAGAATTTAAGGTG 60 GAAGATGACATTTAATGGATCCTGCAGTAGTGTTTGCACATGGAAGTCCAAAAACCTGAA 120 AGGAATATTTCAGTTCAGAGTAGTAGCTGCAAATAATCTAGGGTTTGGTGAATATAGTGG 180 AATCAGTGAGAATATTATATTAGTTGGAGGTATGTTAC218 (2) INFORMATION FOR SEQ ID NO:21: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5084 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21: GATCCCATCGCAGCTACCGCGATGAGAGGCGCTCGCGGCGCCTGGGATTTTCTCTGCGTT 60 CTGCTCCTACTGCTTCGCGTCCAGACAGGCTCTTCTCAACCATCTGTGAGTCCAGGGGAA 120 CCGTCTCCACCATCCATCCATCCAGGAAAATCAGACTTAATAGTCCGCGTGGGCGACGAG 180 ATTAGGCTGTTATGCACTGATCCGGGCTTTGTCAAATGGACTTTTGAGATCCTGGATGAA 240 ACGAATGAGAATAAGCAGAATGAATGGATCACGGAAAAGGCAGAAGCCACCAACACCGGC 300 AAATACACGTGCACCAACAAACACGGCTTAAGCAATTCCATTTATGTGTTTGTTAGAGAT 360 CCTGCCAAGCTTTTCCTTGTTGACCGCTCCTTGTATGGGAAAGAAGACAACGACACGCTG 420 GTCCGCTGTCCTCTCACAGACCCAGAAGTGACCAATTATTCCCTCAAGGGGTGCCAGGGG 480 AAGCCTCTTCCCAAGGACTTGAGGTTTATTCCTGACCCCAAGGCGGGCATCATGATCAAA 540 AGTGTGAAACGCGCCTACCATCGGCTCTGTCTGCATTGTTCTGTGGACCAGGAGGGCAAG 600 TCAGTGCTGTCGGAAAAATTCATCCTGAAAGTGAGGCCAGCCTTCAAAGCTGTGCCTGTT 660 GTGTCTGTGTCCAAAGCAAGCTATCTTCTTAGGGAAGGGGAAGAATTCACAGTGACGTGC 720 ACAATAAAAGATGTGTCTAGTTCTGTGTACTCAACGTGGAAAAGAGAAAACAGTCAGACT 780 AAACTACAGGAGAAATATAATAGCTGGCATCACGGTGACTTCAATTATGAACGTCAGGCA 840 ACGTTGACTATCAGTTCAGCGAGAGTTAATGATTCTGGAGTGTTCATGTGTTATGCCAAT 900 AATACTTTTGGATCAGCAAATGTCACAACAACCTTGGAAGTAGTAGATAAAGGATTCATT 960 AATATCTTCCCCATGATAAACACTACAGTATTTGTAAACGATGGAGAAAATGTAGATTTG 1020 ATTGTTGAATATGAAGCATTCCCCAAACCTGAACACCAGCAGTGGATCTATATGAACAGA 1080 ACCTTCACTGATAAATGGGAAGATTATCCCAAGTCTGAGAATGAAAGTAATATCAGATAC 1140 GTAAGTGAACTTCATCTAACGAGATTAAAAGGCACCGAAGGAGGCACTTACACATTCCTA 1200 GTGTCCAATTCTGACGTCAATGCTGCCATAGCATTTAATGTTTATGTGAATACAAAACCA 1260 GAAATCCTGACTTACGACAGGCTCGTGAATGGCATGCTCCAATGTGTGGCAGCAGGATTC 1320 CCAGAGCCCACAATAGATTGGTATTTTTGTCCAGGAACTGAGCAGAGATGCTCTGCTTCT 1380 GTACTGCCAGTGGATGTGCAGACACTAAACTCATCTGGGCCACCGTTTGGAAAGCTAGTG 1440 GTTCAGAGTTCTATAGATTCTAGTGCATTCAAGCACAATGGCACGGTTGAATGTAAGGCT 1500 TACAACGATGTGGGCAAGACTTCTGCCTATTTTAACTTTGCATTTAAAGGTAACAACAAA 1560 GAGCAAATCCATCCCCACACCCTGTTCACTCCTTTGCTGATTGGTTTCGTAATCGTAGCT 1620 GGCATGATGTGCATTATTGTGATGATTCTGACCTACAAATATTTACAGAAACCCATGTAT 1680 GAAGTACAGTGGAAGGTTGTTGAGGAGATAAATGGAAACAATTATGTTTACATAGACCCA 1740 ACACAACTTCCTTATGATCACAAATGGGAGTTTCCCAGAAACAGGCTGAGTTTTGGGAAA 1800 ACCCTGGGTGCTGGAGCTTTCGGGAAGGTTGTTGAGGCAACTGCTTATGGCTTAATTAAG 1860 TCAGATGCGGCCATGACTGTCGCTGTAAAGATGCTCAAGCCGAGTGCCCATTTGACAGAA 1920 CGGGAAGCCCTCATGTCTGAACTCAAAGTCCTGAGTTACCTTGGTAATCACATGAATATT 1980 GTGAATCTACTTGGAGCCTGCACCATTGGAGGGCCCACCCTGGTCATTACAGAATATTGT 2040 TGCTATGGTGATCTTTTGAATTTTTTGAGAAGAAAACGTGATTCATTTATTTGTTCAAAG 2100 CAGGAAGATCATGCAGAAGCTGCACTTTATAAGAATCTTCTGCATTCAAAGGAGTCTTCC 2160 TGCAGCGATAGTACTAATGAGTACATGGACATGAAACCTGGAGTTTCTTATGTTGTCCCA 2220 ACCAAGGCCGACAAAAGGAGATCTGTGAGAATAGGCTCATACATAGAAAGAGATGTGACT 2280 CCCGCCATCATGGAGGATGACGAGTTGGCCCTAGACTTAGAAGACTTGCTGAGCTTTTCT 2340 TACCAGGTGGCAAAGGGCATGGCTTTCCTCGCCTCCAAGAATTGTATTCACAGAGACTTG 2400 GCAGCCAGAAATATCCTCCTTACTCATGGTCGGATCACAAAGATTTGTGATTTTGGTCTA 2460 GCCAGAGACATCAAGAATGATTCTAATTATGTGGTTAAAGGAAACGCTCGACTACCTGTG 2520 AAGTGGATGGCACCTGAAAGCATTTTCAACTGTGTATACACGTTTGAAAGTGACGTCTGG 2580 TCCTATGGGATTTTTCTTTGGGAGCTGTTCTCTTTAGGAAGCAGCCCCTATCCTGGAATG 2640 CCGGTCGATTCTAAGTTCTACAAGATGATCAAGGAAGGCTTCCGGATGCTCAGCCCTGAA 2700 CACGCACCTGCTGAAATGTATGACATAATGAAGACTTGCTGGGATGCAGATCCCCTAAAA 2760 AGACCAACATTCAAGCAAATTGTTCAGCTAATTGAGAAGCAGATTTCAGAGAGCACCAAT 2820 CATATTTACTCCAACTTAGCAAACTGCAGCCCCAACCGACAGAAGCCCGTGGTAGACCAT 2880 TCTGTGCGGATCAATTCTGTCGGCAGCACCGCTTCCTCCTCCCAGCCTCTGCTTGTGCAC 2940 GACGATGTCTGAGCAGAATCAGTGTTTGGGTCACCCCTCCAGGAATGATCTCTTCTTTTG 3000 GCTTCCATGATGGTTATTTTCTTTTCTTTCAACTTGCATCCAACTCCAGGATAGTGGGCA 3060 CCCCACTGCAATCCTGTCTTTCTGAGCACACTTTAGTGGCCGATGATTTTTGTCATCAGC 3120 CACCATCCTATTGCAAAGGTTCCAACTGTATATATTCCCAATAGCAACGTAGCTTCTACC 3180 ATGAACAGAAAACATTCTGATTTGGAAAAAGAGAGGGAGGTATGGACTGGGGGCCAGAGT 3240 CCTTTCCAAGGCTTCTCCAATTCTGCCCAAAAATATGGTTGATAGTTTACCTGAATAAAT 3300 GGTAGTAATCACAGTTGGCCTTCAGAACCATCCATAGTAGTATGATGATACAAGATTAGA 3360 AGCTGAAAACCTAAGTCCTTTATGTGGAAAACAGAACATCATTAGAACAAAGGACAGAGT 3420 ATGAACACCTGGGCTTAAGAAATCTAGTATTTCATGCTGGGAATGAGACATAGGCCATGA 3480 AAAAAATGATCCCCAAGTGTGAACAAAAGATGCTCTTCTGTGGACCACTGCATGAGCTTT 3540 TATACTACCGACCTGGTTTTTAAATAGAGTTTGCTATTAGAGCATTGAATTGGAGAGAAG 3600 GCCTCCCTAGCCAGCACTTGTATATACGCATCTATAAATTGTCCGTGTTCATACATTTGA 3660 GGGGAAAACACCATAAGGTTTCGTTTCTGTATACAACCCTGGCATTATGTCCACTGTGTA 3720 TAGAAGTAGATTAAGAGCCATATAAGTTTGAAGGAAACAGTTAATACCATTTTTTAAGGA 3780 AACAATATAACCACAAAGCACAGTTTGAACAAAATCTCCTCTTTTAGCTGATGAACTTAT 3840 TCTGTAGATTCTGTGGAACAAGCCTATCAGCTTCAGAATGGCATTGTACTCAATGGATTT 3900 GATGCTGTTTGACAAAGTTACTGATTCACTGCATGGCTCCCACAGGAGTGGGAAAACACT 3960 GCCATCTTAGTTTGGATTCTTATGTAGCAGGAAATAAAGTATAGGTTTAGCCTCCTTCGC 4020 AGGCATGTCCTGGACACCGGGCCAGTATCTATATATGTGTATGTACGTTTGTATGTGTGT 4080 AGACAAATATTTGGAGGGGTATTTTTGCCCTGAGTCCAAGAGGGTCCTTTAGTACCTGAA 4140 AAGTAACTTGGCTTTCATTATTAGTACTGCTCTTGTTTCTTTTCACATAGCTGTCTAGAG 4200 TAGCTTACCAGAAGCTTCCATAGTGGTGCAGAGGAAGTGGAAGGCATCAGTCCCTATGTA 4260 TTTGCAGTTCACCTGCACTTAAGGCACTCTGTTATTTAGACTCATCTTACTGTACCTGTT 4320 CCTTAGACCTTCCATAATGCTACTGTCTCACTGAAACATTTAAATTTTACCCTTTAGACT 4380 GTAGCCTGGATATTATTCTTGTAGTTTACCTCTTTAAAAACAAAACAAAACAAAACAAAA 4440 AACTCCCCTTCCTCACTGCCCAATATAAAAGGCAAATGTGTACATGGCAGAGTTTGTGTG 4500 TTGTCTTGAAAGATTCAGGTATGTTGCCTTTATGGTTTCCCCCTTCTACATTTCTTAGAC 4560 TACATTTAGAGAACTGTGGCCGTTATCTGGAAGTAACCATTTGCACTGGAGTTCTATGCT 4620 CTCGCACCTTTCCAAAGTTAACAGATTTTGGGGTTGTGTTGTCACCCAAGAGATTGTTGT 4680 TTGCCATACTTTGTCTGAAAAATTCCTTTGTGTTTCTATTGACTTCAATGATAGTAAGAA 4740 AAGTGGTTGTTAGTTATAGATGTCTAGGTACTTCAGGGGCACTTCATTGAGAGTTTTGTC 4800 TTGCCATACTTTGTCTGAAAAATTCCTTTGTGTTTCTATTGACTTCAATGATAGTAAGAA 4860 AAGTGGTTGTTAGTTATAGATGTCTAGGTACTTCAGGGGCACTTCATTGAGAGTTTTGTC 4920 AATGTCTTTTGAATATTCCCAAGCCCATGAGTCCTTGAAAATATTTTTTATATATACAGT 4980 AACTTTATGTGTAAATACATAAGCGGCGTAAGTTTAAAGGATGTTGGTGTTCCACGTGTT 5040 TTATTCCTGTATGTTGTCCAATTGTTGACAGTTCTGAAGAATTC5084 (2) INFORMATION FOR SEQ ID NO:22: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4626 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22: GAATTCCGCCCTCGCCGCCCGCGGCGCCCCGAGCGCTTTGTGAGCAGATGCGGAGCCGAG 60 TGGAGGGCGCGAGCCAGATGCGGGGCGACAGCTGACTTGCTGAGAGGAGGCGGGGAGGCG 120 CGGAGCGCGCGTGTGGTCCTTGCGCCGCTGACTTCTCCACTGGTTCCTGGGCACCGAAAG 180 ATAAACCTCTCATAATGAAGGCCCCCGCTGTGCTTGCACCTGGCATCCTCGTGCTCCTGT 240 TTACCTTGGTGCAGAGGAGCAATGGGGAGTGTAAAGAGGCACTAGCAAAGTCCGAGATGA 300 ATGTGAATATGAAGTATCAGCTTCCCAACTTCACCGCGGAAACACCCATCCAGAATGTCA 360 TTCTACATGAGCATCACATTTTCCTTGGTGCCACTAACTACATTTATGTTTTAAATGAGG 420 AAGACCTTCAGAAGGTTGCTGAGTACAAGACTGGGCCTGTGCTGGAACACCCAGATTGTT 480 TCCCATGTCAGGACTGCAGCAGCAAAGCCAATTTATCAGGAGGTGTTTGGAAAGATAACA 540 TCAACATGGCTCTAGTTGTCGACACCTACTATGATGATCAACTCATTAGCTGTGGCAGCG 600 TCAACAGAGGGACCTGCCAGCGACATGTCTTTCCCCACAATCATACTGCTGACATACAGT 660 CGGAGGTTCACTGCATATTCTCCCCACAGATAGAAGAGCCCAGCCAGTGTCCTGACTGTG 720 TGGTGAGCGCCCTGGGAGCCAAAGTCCTTTCATCTGTAAAGGACCGGTTCATCAACTTCT 780 TTGTAGGCAATACCATAAATTCTTCTTATTTCCCAGATCATCCATTGCATTCGATATCAG 840 TGAGAAGGCTAAAGGAAACGAAAGATGGTTTTATGTTTTTGACGGACCAGTCCTACATTG 900 ATGTTTTACCTGAGTTCAGAGATTCTTACCCCATTAAGTATGTCCATGCCTTTGAAAGCA 960 ACAATTTTATTTACTTCTTGACGGTCCAAAGGGAAACTCTAGATGCTCAGACTTTTCACA 1020 CAAGAATAATCAGGTTCTGTTCCATAAACTCTGGATTGCATTCCTACATGGAAATGCCTC 1080 TGGAGTGTATTCTCACAGAAAAGAGAAAAAAGAGATCCACAAAGAAGGAAGTGTTTAATA 1140 TACTTCAGGCTGCGTATGTCAGCAAGCCTGGGGCCCAGCTTGCTAGACAAATAGGAGCCA 1200 GCCTGAATGATGACATTCTTTTCGGGGTGTTCGCACAAAGCAAGCCAGATTCTGCCGAAC 1260 CAATGGATCGATCTGCCATGTGTGCATTCCCTATCAAATATGTCAACGACTTCTTCAACA 1320 AGATCGTCAACAAAAACAATGTGAGATGTCTCCAGCATTTTTACGGACCCAATCATGAGC 1380 ACTGCTTTAATAGGACACTTCTGAGAAATTCATCAGGCTGTGAAGCGCGCCGTGATGAAT 1440 ATCGAACAGAGTTTACCACAGCTTTGCAGCGCGTTGACTTATTCATGGGTCAATTCAGCG 1500 AAGTCCTCTTAACATCTATATCCACCTTCATTAAAGGAGACCTCACCATAGCTAATCTTG 1560 GGACATCAGAGGGTCGCTTCATGCAGGTTGTGGTTTCTCGATCAGGACCATCAACCCCTC 1620 ATGTGAATTTTCTCCTGGACTCCCATCCAGTGTCTCCAGAAGTGATTGTGGAGCATACAT 1680 TAAACCAAAATGGCTACACACTGGTTATCACTGGGAAGAAGATCACGAAGATCCCATTGA 1740 ATGGCTTGGGCTGCAGACATTTCCAGTCCTGCAGTCAATGCCTCTCTGCCCCACCCTTTG 1800 TTCAGTGTGGCTGGTGCCACGACAAATGTGTGCGATCGGAGGAATGCCTGAGCGGGACAT 1860 GGACTCAACAGATCTGTCTGCCTGCAATCTACAAGGTTTTCCCAAATAGTGCACCCCTTG 1920 AAGGAGGGACAAGGCTGACCATATGTGGCTGGGACTTTGGATTTCGGAGGAATAATAAAT 1980 TTGATTTAAAGAAAACTAGAGTTCTCCTTGGAAATGAGAGCTGCACCTTGACTTTAAGTG 2040 AGAGCACGATGAATACATTGAAATGCACAGTTGGTCCTGCCATGAATAAGCATTTCAATA 2100 TGTCCATAATTATTTCAAATGGCCACGGGACAACACAATACAGTACATTCTCCTATGTGG 2160 ATCCTGTAATAACAAGTATTTCGCCGAAATACGGTCCTATGGCTGGTGGCACTTTACTTA 2220 CTTTAACTGGAAATTACCTAAACAGTGGGAATTCTAGACACATTTCAATTGGTGGAAAAA 2280 CATGTACTTTAAAAAGTGTGTCAAACAGTATTCTTGAATGTTATACCCCAGCCCAAACCA 2340 TTTCAACTGAGTTTGCTGTTAAATTGAAAATTGACTTAGCCAACCGAGAGACAAGCATCT 2400 TCAGTTACCGTGAAGATCCCATTGTCTATGAAATTCATCCAACCAAATCTTTTATTAGTA 2460 CTTGGTGGAAAGAACCTCTCAACATTGTCAGTTTTCTATTTTGCTTTGCCAGTGGTGGGA 2520 GCACAATAACAGGTGTTGGGAAAAACCTGAATTCAGTTAGTGTCCCGAGAATGGTCATAA 2580 ATGTGCATGAAGCAGGAAGGAACTTTACAGTGGCATGTCAACATCGCTCTAATTCAGAGA 2640 TAATCTGTTGTACCACTCCTTCCCTGCAACAGCTGAATCTGCAACTCCCCCTGAAAACCA 2700 AAGCCTTTTTCATGTTAGATGGGATCCTTTCCAAATACTTTGATCTCATTTATGTACATA 2760 ATCCTGTGTTTAAGCCTTTTGAAAAGCCAGTGATGATCTCAATGGGCAATGAAAATGTAC 2820 TGGAAATTAAGGGAAATGATATTGACCCTGAAGCAGTTAAAGGTGAAGTGTTAAAAGTTG 2880 GAAATAAGAGCTGTGAGAATATACACTTACATTCTGAAGCCGTTTTATGCACGGTCCCCA 2940 ATGACCTGCTGAAATTGAACAGCGAGCTAAATATAGAGTGGAAGCAAGCAATTTCTTCAA 3000 CCGTCCTTGGAAAAGTAATAGTTCAACCAGATCAGAATTTCACAGGATTGATTGCTGGTG 3060 TTGTCTCAATATCAACAGCACTGTTATTACTACTTGGGTTTTTCCTGTGGCTGAAAAAGA 3120 GAAAGCAAATTAAAGATCTGGGCAGTGAATTAGTTCGCTACGATGCAAGAGTACACACTC 3180 CTCATTTGGATAGGCTTGTAAGTGCCCGAAGTGTAAGCCCAACTACAGAAATGGTTTCAA 3240 ATGAATCTGTAGACTACCGAGCTACTTTTCCAGAAGATCAGTTTCCTAATTCATCTCAGA 3300 ACGGTTCATGCCGACAAGTGCAGTATCCTCTGACAGACATGTCCCCCATCCTAACTAGTG 3360 GGGACTCTGATATATCCAGTCCATTACTGCAAAATACTGTCCACATTGACCTCAGTGCTC 3420 TAAATCCAGAGCTGGTCCAGGCAGTGCAGCATGTAGTGATTGGGCCCAGTAGCCTGATTG 3480 TGCATTTCAATGAAGTCATAGGAAGAGGGCATTTTGGTTGTGTATATCATGGGACTTTGT 3540 TGGACAATGATGGCAAGAAAATTCACTGTGCTGTGAAATCCTTGAACAGAATCACTGACA 3600 TAGGAGAAGTTTCCCAATTTCTGACCGAGGGAATCATCATGAAAGATTTTAGTCATCCCA 3660 ATGTCCTCTCGCTCCTGGGAATCTGCCTGCGAAGTGAAGGGTCTCCGCTGGTGGTCCTAC 3720 CATACATGAAACATGGAGATCTTCGAAATTTCATTCGAAATGAGACTCATAATCCAACTG 3780 TAAAAGATCTTATTGGCTTTGGTCTTCAAGTAGCCAAAGCGATGAAATATCTTGCAAGCA 3840 AAAAGTTTGTCCACAGAGACTTGGCTGCAAGAAACTGTATGCTGGATGAAAAATTCACAG 3900 TCAAGGTTGCTGATTTTGGTCTTGCCAGAGACATGTATGATAAAGAATACTATAGTGTAC 3960 ACAACAAAACAGGTGCAAAGCTGCCAGTGAAGTGGATGGCTTTGGAAAGTCTGCAAACTC 4020 AAAAGTTTACCACCAAGTCAGATGTGTGGTCCTTTGGCGTCGTCCTCTGGGAGCTGATGA 4080 CAAGAGGAGCCCCACCTTATCCTGACGTAAACACCTTTGATATAACTGTTTACTTGTTGC 4140 AAGGGAGAAGACTCCTACAACCCGAATACTGCCCAGACCCCTTATATGAAGTAATGCTAA 4200 AATGCTGGCACCCTAAAGCCGAAATGCGCCCATCCTTTTCTGAACTGGTGTCCCGGATAT 4260 CAGCGATCTTCTCTACTTTCATTGGGGAGCACTATGTCCATGTGAACGCTACTTATGTGA 4320 ACGTAAAATGTGTCGCTCCGTATCCTTCTCTGTTGTCATCAGAAGATAACGCTGATGATG 4380 AGGTGGACACACGACCAGCCTCCTTCTGGGAGACATCATAGTGCTAGTACTATGTCAAAG 4440 CAACAGTCCACACTTTGTCCAATGGTTTTTTCACTGCCTGACCTTTAAAAGGCCATCGAT 4500 ATTCTTTGCTCCTTGCCATAGGACTTGTATTGTTATTTAAATTACTGGATTCTAAGGAAT 4560 TTCTTATCTGACAGAGCATCAGAACCAGAGGCTTGGTCCCACAGGCCAGGGACCAATGCG 4620 CTGCAG4626 (2) INFORMATION FOR SEQ ID NO:23: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2301 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23: GTCGACCGGAGGGCAGGAGGAGCAGGAGGAGCAGGAGCAGGAGGAGCAGGAGGAGCAGGA 60 GGAGCAGGAGGAGCAGGAGGAGCAGGAACAGGAGGAGGAGGAGGAGGAGAAGGAGGAGCA 120 GGAAGAGCAGGAGGAGGAGGAGCAGGAGCAGGAGGAGCAGGAGGGAGAGGAGGCTGCAAC 180 GCCGAGCGGAGGAGGCAGGAACCGGAGCGCGAGCAGTAGCTGGGTGGGCACCATGGCTGG 240 GATCACCACCATCGAGGCGGTGAAGCGCAAGATCCAGGTTCTGCAGCAGCAGGCAGATGA 300 TGCAGAGGAGCGAGCTGAGCGCCTCCAGCGAGAAGTTGAGGGAGAAAGGCGGGCCCGGGA 360 ACAGGCTGAGGCTGAGGTGGCCTCCTTGAACCGTAGGATCCAGCTGGTTGAAGAAGAGCT 420 GGACCGTGCTCAGGAGCGCCTGGCCACTGCCCTGCAAAAGCTGGAAGAAGCTGAAAAAGC 480 TGCTGATGAGAGTGAGAGAGGTATGAAGGTTATTGAAAACCGGGCCTTAAAAGATGAAGA 540 AAAGATGGAACTCCAGGAAATCCAACTCGAAGAAGCTAAGCACATTGCAGAAGAGGCAGA 600 TAGGAAGTATGAAGAGGTGGCTCGTAAGTTGGTGATCATTGAAGGAGACTTGGAACGCAC 660 AGAGGAACGAGCTGAGCTGGCAGAGTCGCGTTGCCGAGAGATGGATGAGCAGATTAGACT 720 GATGGACCAGAACCTGAAGTGTCTGAGTGCTGCCGAAGAAAAGTACTCTCAAAAAGAAGA 780 TAAATATGAGGAAGAAATCAAGATTCTTACTGATAAACTCAAGGAGGCAGAGACCCGTGC 840 TGAGTTTGCTGAGAGATCGGTAGCCAAGCTGGAAAAGACAATTGATGACCTGGAAGACAC 900 TAACAGCACATCTGGAGACCCGGTGGAGAAGAAGGACGAAACACCTTTTGGGGTCTCGGT 960 GGCTGTGGGCCTGGCCGTCTTTGCCTGCCTCTTCCTTTCTACGCTGCTCCTTGTGCTCAA 1020 CAAATGTGGACGGAGAAACAAGTTTGGGATCAACCGCCCGGCTGTGCTGGCTCCAGAGGA 1080 TGGGCTGGCCATGTCCCTGCATTTCATGACATTGGGTGGCAGCTCCCTGTCCCCCACCGA 1140 GGGCAAAGGCTCTGGGCTCCAAGGCCACATCATCGAGAACCCACAATACTTCAGTGATGC 1200 CTGTGTTCACCACATCAAGCGCCGGGACATCGTGCTCAAGTGGGAGCTGGGGGAGGGCGC 1260 CTTTGGGAAGGTCTTCCTTGCTGAGTGCCACAACCTCCTGCCTGAGCAGGACAAGATGCT 1320 GGTGGCTGTCAAGGCACTGAAGGAGGCGTCCGAGAGTGCTCGGCAGGACTTCCAACGTGA 1380 GGCTGAGCTGCTCACCATGCTGCAGCACCAGCACATCGTGCGCTTCTTCGGCGTCTGCAC 1440 CGAGGGCCGCCCCCTGCTCATGGTCTTCGAGTATATGCGGCACGGGGACCTCAACCGCTT 1500 CCTCCGATCCCATGGACCCGATGCCAAGCTGCTGGCTGGTGGGGAGGATGTGGCTCCAGG 1560 CCCCCTGGGTCTGGGGCAGCTGCTGGCCGTGGCTAGCCAGGTCGCTGCGGGGATGGTGTA 1620 CCTGGCGGGTCTGCATTTTGTGCACCGGGACCTGGCCACACGCAACTGTCTAGTGGGCCA 1680 GGGACTGGTGGTCAAGATTGGTGATTTTGGCATGAGCAGGGATATCTACAGCACCGACTA 1740 TTACCGTGTGGGAGGCCGCACCATGCTGCCCATTCGCTGGATGCCGCCCGAGAGCATCCT 1800 GTACCGTAAGTTCACCACCGAGAGCGACGTGTGGAGCTTCGGCGTGGTGCTCTGGGAGAT 1860 CTTCACCTACGGCAAGCAGCCCTGGTACCAGCTCTCCAACACGGAGGCAATCGACTGCAT 1920 CACGCAGGGACGTGAGTTGGAGCGGCCACGTGCCTGCCCACCAGAGGTCTACGCCATCAT 1980 GCGGGGCTGCTGGCAGCGGGAGCCCAGCAACGCCACAGCATCAAGGATGTGCACGCCCGG 2040 CTGCAAGCCCTGGCCTAGGCACCTCCTGTCTACCTGGATGTCCTGGGCTAGGGGGCCGGC 2100 CCAGGGGCTGGGAGTGGTTAGCCGGAATACTGGGGCCTGCCCTCAGCATCCCCCATAGCT 2160 CCCAGCAGCCCCAGGGTGATCTCGAAGTATCTAATTCGCCCTCAGCATGTGGGAAGGGAC 2220 AGGTGGGGGCTGGGAGTAGAGGATGTTCCTGCTTCTCTAGGCAAGGTCCCGTCGTAGCAA 2280 TTATATTTATTATGGGAATTC2301 (2) INFORMATION FOR SEQ ID NO:24: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 271 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24: CTGCCAGGACCATGGGTAGCAACAAGAGCAAGCCCAAGGATGCCAGCCAGCGGCGCCGCA 60 GCCTGGAGCCCGCCGAGAACGTGCACGGCGCTGGCGGGGGCGCTTTCCCCGCCTCGCAGA 120 CCCCCAGCAAGCCAGCCTCGGCCGACGGCCACCGCGGCCCCAGCGCGGCCTTCGCCCCCG 180 CGGCCGCCGAGCCCAAGCTGTTCGGAGGCTTCAACTCCTCGGACACCGTCACCTCCCCGC 240 AGAGGGCGGGCCCGCTGGCCGGTCAGTGCGC271 (2) INFORMATION FOR SEQ ID NO:25: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 118 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25: CTCTCTGCAGGTGGAGTGACCACCTTTGTGGCCCTCTATGACTATGAGTCTAGGACGGAG 60 ACAGACCTGTCCTTCAAGAAAGGCGAGCGGCTCCAGATTGTCAACAACACGTGAGTGC11 8 (2) INFORMATION FOR SEQ ID NO:26: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 113 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26: CCTGCTCAGAGAGGGAGACTGGTGGCTGGCCCACTCGCTCAGCACAGGACAGACAGGCTA 60 CATCCCCAGCAACTACGTGGCGCCCTCCGACTCCATCCAGGCTGAGGAGTTAG113 (2) INFORMATION FOR SEQ ID NO:27: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 115 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27: CCCCCAGGTGGTATTTTGGCAAGATCACCAGACGGGAGTCAGAGCGGTTACTGCTCAATG 60 CAGAGAACCCGAGAGGGACCTTCCTCGTGCGAGAAAGTGAGACCACGAAAGGTAC115 (2) INFORMATION FOR SEQ ID NO:28: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 164 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28: GCCCCGCAGGTGCCTACTGCCTCTCAGTGTCTGACTTCGACAACGCCAAGGGCCTCAACG 60 TGAAGCACTACAAGATCCGCAAGCTGGACAGCGGCGGCTTCTACATCACCTCCCGCACCC 120 AGTTCAACAGCCTGCAGCAGCTGGTGGCCTACTACTCCAGTGAG164 (2) INFORMATION FOR SEQ ID NO:29: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 170 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29: CCTCCTCAGAACACGCCGATGGCCTGTGCCACCGCCTCACCACCGTGTGCCCCACGTCCA 60 AGCCGCAGACTCAGGGCCTGGCCAAGGATGCCTGGGAGATCCCTCGGGAGTCGCTGCGGC 120 TGGAGGTCAAGCTGGGCCAGGGCTGCTTTGGCGAGGTGTGGATGGGTAAG170 (2) INFORMATION FOR SEQ ID NO:30: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 194 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30: CCTCAACAGGGACCTGGAACGGTACCACCAGGGTGGCCATCAAAACCCTGAAGCCTGGCA 60 CGATGTCTCCAGAGGCCTTCCTGCAGGAGGCCCAGGTCATGAAGAAGCTGAGGCATGAGA 120 AGCTGGTGCAGTTGTATGCTGTGGTTTCAGAGGAGCCCATTTACATCGTCACGGAGTACA 180 TGAGCAAGGGTGAG194 (2) INFORMATION FOR SEQ ID NO:31: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 91 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31: TCTGCCCAGGGAGTTTGCTGGACTTTCTCAAGGGGGAGACAGGCAAGTACCTGCGGCTGC 60 CTCAGCTGGTGGACATGGCTGCTCAGGTGAG91 (2) INFORMATION FOR SEQ ID NO:32: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 165 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32: CTGCAGATCGCCTCAGGCATGGCGTACGTGGAGCGGATGAACTACGTCCACCGGGACCTT 60 CGTGCAGCCAACATCCTGGTGGGAGAGAACCTGGTGTGCAAAGTGGCCGACTTTGGGCTG 120 GCTCGGCTCATTGAAGACAATGAGTACACGGCGCGGCAAGGTGGG165 (2) INFORMATION FOR SEQ ID NO:33: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 146 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33: TTCCTGCAGGTGCCAAATTCCCCATCAAGTGGACGGCTCCAGAAGCTGCCCTCTATGGCC 60 GCTTCACCATCAAGTCGGACGTGTGGTCCTTCGGGATCCTGCTGACTGAGCTCACCACAA 120 AGGGACGGGTGCCCTACCCTGGTAAG146 (2) INFORMATION FOR SEQ ID NO:34: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 255 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34: CTGCCACAGGGATGGTGAACCGCGAGGTGCTGGACCAGGTGGAGCGGGGCTACCGGATGC 60 CCTGCCCGCCGGAGTGTCCCGAGTCCCTGCACGACCTCATGTGCCAGTGCTGGCGGAAGG 120 AGCCTGAGGAGCGGCCCACCTTCGAGTACCTGCAGGCCTTCCTGGAGGACTACTTCACGT 180 CCACCGAGCCCCAGTACCAGCCCGGGGAGAACCTCTAGGCACAGGCGGGCCCAGACCGGC 240 TTCTCGGCTTGGATC255 (2) INFORMATION FOR SEQ ID NO:35: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 3623 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35: CGCGGCCGCCCTGGGCGGGCGCGGGCGGCGGGCGGCGGTGAGGGCGGCCTGCGGGGCGGC 60 GCCCGGGGGCCGGGCCGAGCCGGGCCTGAGCCGGGCCCGGACCGAGCTGGGAGAGGGGCT 120 CCGGCCCGATCGTTCGCTTGGCGCAAAATGTTGGAGATCTGCCTGAAGCTGGTGGGCTGC 180 AAATCCAAGAAGGGGCTGTCCTCGTCCTCCAGCTGTTATCTGGAAGAAGCCCTTCAGCGG 240 CCAGTAGCATCTGACTTTGAGCCTCAGGGTCTGAGTGAAGCCGCTCGTTGGAACTCCAAG 300 GAAAACCTTCTCGCTGGACCCAGTGAAAATGACCCCAACCTTTTCGTTGCACTGTATGAT 360 TTTGTGGCCAGTGGAGATAACACTCTAAGCATAACTAAAGGTGAAAAGCTCCGGGTCTTA 420 GGCTATAATCACAATGGGGAATGGTGTGAAGCCCAAACCAAAAATGGCCAAGGCTGGGTC 480 CCAAGCAACTACATCACGCCAGTCAACAGTCTGGAGAAACACTCCTGGTACCATGGGCCT 540 GTGTCCCGCAATGCCGCTGAGTATCCGCTGAGCAGCGGGATCAATGGCAGCTTCTTGGTG 600 CGTGAGAGTGAGAGCAGTCCTAGCCAGAGGTCCATCTCGCTGAGATACGAAGGGAGGGTG 660 TACCATTACAGGATCAACACTGCTTCTGATGGCAAGCTCTACGTCTCCTCCGAGAGCCGC 720 TTCAACACCCTGGCCGAGTTGGTTCATCATCATTCAACGGTGGCCGACGGGCTCATCACC 780 ACGCTCCATTATCCAGCCCCAAAGCGCAACAAGCCCACTGTCTATGGTGTGTCCCCCAAC 840 TACGACAAGTGGGAGATGGAACGCACGGACATCACCATGAAGCACAAGCTGGGCGGGGGC 900 CAGTACGGGGAGGTGTACGAGGGCGTGTGGAAGAAATACAGCCTGACGGTGGCCGTGAAG 960 ACCTTGAAGGAGGACACCATGGAGGTGGAAGAGTTCTTGAAAGAAGCTGCAGTCATGAAA 1020 GAGATCAAACACCCTAACCTAGTGCAGCTCCTTGGGGTCTGCACCCGGGAGCCCCCGTTC 1080 TATATCATCACTGAGTTCATGACCTACGGGAACCTCCTGGACTACCTGAGGGAGTGCAAC 1140 CGGCAGGAGGTGAACGCCGTGGTGCTGCTGTACATGGCCACTCAGATCTCGTCAGCCATG 1200 GAGTACCTAGAGAAGAAAAACTTCATCCACAGAGATCTTGCTGCCCGAAACTGCCTGGTA 1260 GGGGAGAACCACTTGGTGAAGGTAGCTGATTTTGGCCTGAGCAGGTTGATGACAGGGGAC 1320 ACCTACACAGCCCATGCTGGAGCCAAGTTCCCCATCAAATGGACTGCACCCGAGAGCCTG 1380 GCCTACAACAAGTTCTCCATCAAGTCCGACGTCTGGGCATTTGGAGTATTGCTTTGGGAA 1440 ATTGCTACCTATGGCATGTCCCCTTACCCGGGAATTGACCGTTCCCAGGTGTATGAGCTG 1500 CTAGAGAAGGACTACCGCATGAAGCGCCCAGAAGGCTGCCCAGAGAAGGTCTATGAACTC 1560 ATGCGAGCATGTTGGCAGTGGAATCCCTCTGACCGGCCCTCCTTTGCTGAAATCCACCAA 1620 GCCTTTGAAACAATGTTCCAGGAATCCAGTATCTCAGACGAAGTGGAAAAGGAGCTGGGG 1680 AAACAAGGCGTCCGTGGGGCTGTGACTACCTTGCTGCAGGCCCCAGAGCTGCCCACCAAG 1740 ACGAGGACCTCCAGGAGAGCTGCAGAGCACAGAGACACCACTGACGTGCCTGAGATGCCT 1800 CACTCCAAGGGCCAGGGAGAGAGCGATCCTCTGGACCATGAGCCTGCCGTGTCTCCATTG 1860 CTCCCTCGAAAAGAGCGAGGTCCCCCGGAGGGCGGCCTGAATGAAGATGAGCGCCTTCTC 1920 CCCAAAGACAAAAAGACCAACTTGTTCAGCGCCTTGATCAAGAAGAAGAAGAAGACAGCC 1980 CCAACCCCTCCCAAACGCAGCAGCTCCTTCCGGGAGATGGACGGCCAGCCGGAGCGCAGA 2040 GGGGCCGGCGAGGAAGAGGGCCGAGACATCAGCAACGGGGCACTGGCTTTCACCCCCTTG 2100 GACACAGCTGACCCAGCCAAGTCCCCAAAGCCCAGCAATGGGGCTGGGGTCCCCAATGGA 2160 GCCCTCCGGGAGTCCGGGGGCTCAGGCTTCCGGTCTCCCCACCTGTGGAAGAAGTCCAGC 2220 ACGCTGACCAGCAGCCGCCTAGCCACCGGCGAGGAGGAGGGCGGTGGCAGCTCCAGCAAG 2280 CGCTTCCTGCGCTCTTGCTCCGTCTCCTGCGTTCCCCATGGGGCCAAGGACACGGAGTGG 2340 AGGTCAGTCACGCTGCCTCGGGACTTGCAGTCCACGGGAAGACAGTTTGACTCGTCCACA 2400 TTTGGAGGGCACAAAAGTGAGAAGCCGGCTCTGCCTCGGAAGAGGGCAGGGGAGAACAGG 2460 TCTGACCAGGTGACCCGAGGCACAGTAACGCCTCCCCCCAGGCTGGTGAAAAAGAATGAG 2520 GAAGCTGCTGATGAGGTCTTCAAAGACATCATGGAGTCCAGCCCGGGCTCCAGCCCGCCC 2580 AACCTGACTCCAAAACCCCTCCGGCGGCAGGTCACCGTGGCCCCTGCCTCGGGCCTCCCC 2640 CACAAGGAAGAAGCCTGGAAAGGCAGTGCCTTAGGGACCCCTGCTGCAGCTGAGCCAGTG 2700 ACCCCCACCAGCAAAGCAGGCTCAGGTGCACCAAGGGGCACCAGCAAGGGCCCCGCCGAG 2760 GAGTCCAGAGTGAGGAGGCACAAGCACTCCTCTGAGTCGCCAGGGAGGGACAAGGGGAAA 2820 TTGTCCAAGCTCAAACCTGCCCCGCCGCCCCCACCAGCAGCCTCTGCAGGGAAGGCTGGA 2880 GGAAAGCCCTCGCAGAGGCCCGGCCAGGAGGCTGCCGGGGAGGCAGTCTTGGGCGCAAAG 2940 ACAAAAGCCACGAGTCTGGTTGATGCTGTGAACAGTGACGCTGCCAAGCCCAGCCAGCCG 3000 GCAGAGGGCCTCAAAAAGCCCGTGCTCCCGGCCACTCCAAAGCCACACCCCGCCAAGCCG 3060 TCGGGGACCCCCATCAGCCCAGCCCCCGTTCCCCTTTCCACGTTGCCATCAGCATCCTCG 3120 GCCTTGGCAGGGGACCAGCCGTCTTCCACTGCCTTCATCCCTCTCATATCAACCCGAGTG 3180 TCTCTTCGGAAAACCCGCCAGCCTCCAGAGCGGGCCAGCGGCGCCATCACCAAGGGCGTG 3240 GTCTTGGACAGCACCGAGGCGCTGTGCCTCGCCATCTCTGGGAACTCCGAGCAGATGGCC 3300 AGCCACAGCGCAGTGCTGGAGGCCGGCAAAAACCTCTACACGTTCTGCGTGAGCTATGTG 3360 GATTCCATCCAGCAAATGAGGAACAAGTTTGCCTTCCGAGAGGCCATCAACAAACTGGAG 3420 AATAATCTCCGGGAGCTTCAGATCTGCCCGGCGTCAGCAGGCAGTGGTCCGGCGGCCACT 3480 CAGGACTTCAGCAAGCTCCTCAGTTCGGTGAAGGAAATCAGTGACATAGTGCAGAGGTAG 3540 CAGCAGTCAGGGGTCAGGTGTCAGGCCCGTCGGAGCTGCCTGCAGCACATGCGGGCTCGC 3600 CCATACCCATGACAGTGGCTGAG3623 (2) INFORMATION FOR SEQ ID NO:36: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 257 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36: CACAGCATTCCGCTGACCATCAATAAGGAAGAAGCCCTTCAGCGGCCAGTAGCATCTGAC 60 TTTGAGCCTCAGGGTCTGAGTGAAGCCGCTCGTTGGAACTCCAAGGAAAACCTTCTCGCT 120 GGACCCAGTGAAAATGACCCCAACCTTTTCGTTGCACTGTATGATTTTGTGGCCAGTGGA 180 GATAACACTCTAAGCATAACTAAAGGTGAAAAGCTCCGGGTCTTAGGCTATAATCACAAT 240 GGGGAATGGTGTGAAGC257 (2) INFORMATION FOR SEQ ID NO:37: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 266 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37: GTCATCGTCCACTCAGCCACTGGATTTAAGCAGAGTTCAAAAGCCCTTCAGCGGCCAGTA 60 GCATCTGACTTTGAGCCTCAGGGTCTGAGTGAAGCCGCTCGTTGGAACTCCAAGGAAAAC 120 CTTCTCGCTGGACCCAGTGAAAATGACCCCAACCTTTTCGTTGCACTGTATGATTTTGTG 180 GCCAGTGGAGATAACACTCTAAGCATAACTAAAGGTGAAAAGCTCCGGGTCTTAGGCTAT 240 AATCACAATGGGGAATGGTGTGAAGC266 (2) INFORMATION FOR SEQ ID NO:38: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 80 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38: GATGGCGAGGGCGCCTTCCATGGAGACGCAGAAGCCCTTCAGCGGCCAGTAGCATCTGAC 60 TTTGAGCCTCAGGGTCTGAG80 (2) INFORMATION FOR SEQ ID NO:39: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 139 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39: GTTCTGTTCTGTGCCTACAGTGAAGGTGACTGGTGGGAGGCTCGGTCTCTCAGCTCCGGA 60 AAAACTGGCTGCATTCCCAGCAACTACGTGGCCCCTGTTGACTCAATCCAAGCTGAAGAG 120 TAAGTAGGGATTGGGGCAA139 (2) INFORMATION FOR SEQ ID NO:40: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1804 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40: GGATCCTCAGGGGTAACACCTTTTGGAGGTGGGCATCTTCCTCATTCTCAGTGGTGCCAA 60 GTTCATATCCTGCTGGCTTAACACGTGGTGTTACTATATTTGTGGCCTTATATGATTATG 120 AAGCTAGAACTACAGAAGACCTTTCATTTAAGAAGGGTGAAAAATTTCAAATAATTAACA 180 ATACAGAAGGAGACTGGTGGGAAGCAAGATCAATCACTACAGGAAAGAATGGTTATATCC 240 TGAGCAGTTATGTAGCGCCTGCAGATTCCATTCAGGCAGAAGAATGGTATTTTGGCAAAA 300 TGGGGAGAAAAGATGCTGAAAGATTACTTCTGAATCCTGGAAATTAATGAGGTATTTTCT 360 TAGGAAGAGAGAGTGAAATGGCTGGGTGCAGTGGCTCATGCCTGTAATCCCAGCACTTTG 420 GGAGGCCGAGTTGGGCGGATCACCTGAGGTCAGGAGTTCGAGACTAGCCTGGCCAACATG 480 GTGAAACCCCATCTCTACTAAAAAAAAAAGTACAAAATTAGCTGGACGTGGTGGTGAGTG 540 CCTGTAATCCCAGCTACTCAGGAGGCTGAGGCAGCAGAATCACTTGAACCTGGGAGGCGG 600 AGGTTGCAGTGAGCTGAGATCGCGCCACTGCACTCCAGCCTCGGCGACAAGAGCAAAAAC 660 TCCGTCTAAAAAACAAATAAGCAAACAGAACAAAACAAAACAAAAACGAGAGAGCGAAAC 720 TACTAAAGGTGCTTATTCCCTCTCTATTCGTGATTGGGATGAGGTAAGGGGTGACAATGT 780 GAAACACCACAAAATTAGGAAACTTGACAATGGTAGATACTATATCACAACCAGAGAACA 840 ACTTGATACTCTGCAGAAATTGGCAAAACACTACACAGAACATGCTGATGGTTTATGCCA 900 CAAGTTAACAACTGTGTGTCCAACTGTGAAACCTCAGATTCAAGGTCTAGCAAAAGATGC 960 TTGGGAAATCCCTTGATAATCTTTGCGACTAGAGGTTAAACTAGGACAAGGATGTTTTGG 1020 CAAAGTGTGGATGGGAATATGGAATGGAACCACAAAAGTAGCAATCAAAACACTAAAACC 1080 AGGTACAATGATGCCAGAAGCTTTTCTTCAAGAAGCTCAGGTAATGAAAAAAATAAGACA 1140 TGGTAAACTTGTTCCACTATATGCTGTTGTTTCTGAAGAGCCAATTTACATTGTCACTGA 1200 ATTGATGTCAAAAGGAAGCTTATTCAATTTCCTTAAGGAAGGAGATGGAAAGTATTTGAA 1260 GCTTCCACAAATGGTTGATATGCCTGCTCAGATTGCTGATGGTATGGCATATATTAAAAG 1320 AATGAACTATATTCACCGAGATCTCTGGGCTGCTAATATTCTTGTAGGAGAAAATCTTCT 1380 GTGCAAAATAGCAGATTTTGGTTTAGCAAGGTTAATTGAAGACAATGAATACACATCAAG 1440 ACAAGGTGCAGAATTTCCAATCAAATGGACAGCTCCTGAAGTTGCACTGTATGGTGGGTT 1500 TACAATAAAGTCTGGTGTCTGCTCATTTGGAATTCTACAGACAGAACTGGTAACAAAGGG 1560 CAGAGTGCCATATCCAGGTATGGTGAACCATGAAATACTGGAACAGGTGGAGCGAGGATA 1620 CAGGATGCCTTGCCCTCAGGGCTGTCCAGAATCCCTCCATGAATTGATGAATCTGTGTTG 1680 GAAGAAGGACCCTGATGAAAGACCAACATTTGAATATGTTCAGTCCTTCTTGGGAGACTA 1740 CTTCACTGCTACAGAGCCATAGTACCAGCCAGGAGAAAACTTCTAATTCAAGTAGCCTAT 1800 TTTA1804 (2) INFORMATION FOR SEQ ID NO:41: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8082 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41: AGCTTGTTTGGCCGTTTTAGGGTTTGTTGGAATTTTTTTTTCGTCTATGTACTTGTGAAT 60 TATTTCACGTTTGCCATTACCGGTTCTCCATAGGGTGATGTTCATTAGCAGTGGTGATAG 120 GTTAATTTTCACCATCTCTTATGCGGTTGAATAGTCACCTCTGAACCACTTTTTCCTCCA 180 GTAACTCCTCTTTCTTCGGACCTTCTGCAGCCAACCTGAAAGAATAACAAGGAGGTGGCT 240 GGAAACTTGTTTTAAGGAACCGCCTGTCCTTCCCCCGCTGGAAACCTTGCACCTCGGACG 300 CTCCTGCTCCTGCCCCCACCTGACCCCCGCCCTCGTTGACATCCAGGCGCGATGATCTCT 360 GCTGCCAGTAGAGGGCACACTTACTTTACTTTCGCAAACCTGAACGCGGGTGCTGCCCAG 420 AGAGGGGGCGGAGGGAAAGACGCTTTGCAGCAAAATCCAGCATAGCGATTGGTTGCTCCC 480 CGCGTTTGCGGCAAAGGCCTGGAGGCAGGAGTAATTTGCAATCCTTAAAGCTGAATTGTG 540 CAGTGCATCGGATTTGGAAGCTACTATATTCACTTAACACTTGAACGCTGAGCTGCAAAC 600 TCAACGGGTAATAACCCATCTTGAACAGCGTACATGCTATACACACACCCCTTTCCCCCG 660 AATTGTTTTCTCTTTTGGAGGTGGTGGAGGGAGAGAAAAGTTTACTTAAAATGCCTTTGG 720 GTGAGGGACCAAGGATGAGAAGAATGTTTTTTGTTTTTCATGCCGTGGAATAACACAAAA 780 TAAAAAATCCCGAGGGAATATACATTATATATTAAATATAGATCATTTCAGGGAGCAAAC 840 AAATCATGTGTGGGGCTGGGCAACTAGCTGAGTCGAAGCGTAAATAAAATGTGAATACAC 900 GTTTGCGGGTTACATACAGTGCACTTTCACTAGTATTCAGAAAAAATTGTGAGTCAGTGA 960 ACTAGGAAATTAATGCCTGGAAGGCAGCCAAATTTTAATTAGCTCAAGACTCCCCCCCCC 1020 CCCCAAAAAAAGGCACGGAAGTAATACTCCTCTCCTCTTCTTTGATCAGAATCGATGCAT 1080 TTTTTGTGCATGACCGCATTTCCAATAATAAAAGGGGAAAGAGGACCTGGAAAGGAATTA 1140 AACGTCCGGTTTGTCCGGGGAGGAAAGAGTTAACGGTTTTTTTCACAAGGGTCTCTGCTG 1200 ACTCCCCCGGCTCGGTCCACAAGCTCTCCACTTGCCCCTTTTAGGAAGTCCGGTCCCGCG 1260 GTTCGGGTACCCCCTGCCCCTCCCATATTCTCCCGTCTAGCACCTTTGATTTCTCCCAAA 1320 CCCGGCAGCCCGAGACTGTTGCAAACCGGCGCCACAGGGCGCAAAGGGGATTTGTCTCTT 1380 CTGAAACCTGGCTGAGAAATTGGGAACTCCGTGTGGGAGGCGTGGGGGTGGGACGGTGGG 1440 GTACAGACTGGCAGAGAGCAGGCAACCTCCCTCTCGCCCTAGCCCAGCTCTGGAACAGGC 1500 AGACACATCTCAGGGCTAAACAGACGCCTCCCGCACGGGGCCCCACGGAAGCCTGAGCAG 1560 GCGGGGCAGGAGGGGCGGTATCTGCTGCTTTGGCAGCAAATTGGGGGACTCAGTCTGGGT 1620 GGAAGGTATCCAATCCAGATAGCTGTGCATACATAATGCATAATACATGACTCCCCCCAA 1680 CAAATGCAATGGGAGTTTATTCATAACGCGCTCTCCAAGTATACGTGGCAATGCGTTGCT 1740 GGGTTATTTTAATCATTCTAGGCATCGTTTTCCTCCTTATGCCTCTATCATTCCTCCCTA 1800 TCTACACTAACATCCCACGCTCTGAACGCGCGCCCATTAATACCCTTCTTTCCTCCACTC 1860 TCCCTGGGACTCTTGATCAAAGCGCGGCCCTTTCCCCAGCCTTAGCGAGGCGCCCTGCAG 1920 CCTGGTACGCGCGTGGCGTGGCGGTGGGCGCGCAGTGCGTTCTCTGTGTGGAGGGCAGCT 1980 GTTCCGCCTGCGATGATTTATACTCACAGGACAAGGATGCGGTTTGTCAAACAGTACTGC 2040 TACGGAGGAGCAGCAGAGAAAGGGAGAGGGTTTGAGAGGGAGCAAAAGAAAATGGTAGGC 2100 GCGCGTAGTTAATTCATGCGGCTCTCTTACTCTGTTTACATCCTAGAGCTAGAGTGCTCG 2160 GCTGCCCGGCTGAGTCTCCTCCCCACCTTCCCCACCCTCCCCACCCTCCCCATAAGCGCC 2220 CCTCCCGGGTTCCCAAAGCAGAGGGCGTGGGGGAAAAGAAAAAAGATCCTCTCTCGCTAA 2280 TCTCCGCCCACCGGCCCTTTATAATGCGAGGGTCTGGACGGCTGAGGACCCCCGAGCTGT 2340 GCTGCTCGCGGCCGCCACCGCCGGGCCCCGGCCGTCCCTGGCTCCCCTCCTGCCTCGAGA 2400 AGGGCAGGGCTTCTCAGAGGCTTGGCGGGAAAAAGAACGGAGGGAGGGATCGCGCTGAGT 2460 ATAAAAGCCGGTTTTCGGGGCTTTATCTAACTCGCTGTAGTAATTCCAGCGAGAGGCAGA 2520 GGGAGCGAGCGGGCGGCCGGCTAGGGTGGAAGAGCCGGGCGAGCAGAGCTGCGCTGCGGG 2580 CGTCCTGGGAAGGGAGATCCGGAGCGAATAGGGGGCTTCGCCTCTGGCCCAGCCCTCCCG 2640 CTGATCCCCCAGCCAGCGGTCCGCAACCCTTGCCGCATCCACGAAACTTTGCCCATAGCA 2700 GCGGGCGGGCACTTTGCACTGGAACTTACAACACCCGAGCAAGGACGCGACTCTCCCGAC 2760 GCGGGGAGGCTATTCTGCCCATTTGGGGACACTTCCCCGCCGCTGCCAGGACCCGCTTCT 2820 CTGAAAGGCTCTCCTTGCAGCTGCTTAGACGCTGGATTTTTTTCGGGTAGTGGAAAACCA 2880 GGTAAGCACCGAAGTCCACTTGCCTTTTAATTTATTTTTTTATCACTTTAATGCTGAGAT 2940 GAGTCGAATGCCTAAATAGGGTGTCTTTTCTCCCATTCCTGCGCTATTGACACTTTTCTC 3000 AGAGTAGTTATGGTAACTGGGGCTGGGGTGGGGGGTAATCCAGAACTGGATCGGGGTAAA 3060 GTGACTTGTCAAGATGGGAGAGGAGAAGGCAGAGGGAAAACGGGAATGGTTTTTAAGACT 3120 ACCCTTTCGAGATTTCTGCCTTATGAATATATTCACGCTGACTCCCGGCCGGTCGGACAT 3180 TCCTGCTTTATTGTGTTAATTGCTCTCTGGGTTTTGGGGGGCTGGGGGTTGCTTTGCGGT 3240 GGGCAGAAAGCCCCTTGCATCCTGAGCTCCTTGGAGTAGGGACCGCATATCGCCTGTGTG 3300 AGCCAGATCGCTCCGCAGCCGCTGACTTGTCCCCGTCTCCGGGAGGGCATTTAAATTTCG 3360 GCTCACCGCATTTCTGACAGCCGGAGACGGACACTGCGGCGCGTCCCGCCCGCCTGTCCC 3420 CGCGGCGATTCCAACCCGCCCTGATCCTTTTAAGAAGTTGGCATTTGGCTTTTTAAAAAG 3480 CAATAATACAATTTAAAACCTGGGTCTCTAGAGGTGTTAGGACGTGGTGTTGGGTAGGCG 3540 CAGGCAGGGGAAAAGGGAGGCGAGGATGTGTCCGATTCTCCTGGAATCGTTGACTTGGAA 3600 AAACCAGGGCGAATCTCCGCACCCAGCCCTGACTCCCCTGCCGCGGCCGCCCTCGGGTGT 3660 CCTCGCGCCCGAGATGCGGAGGAACTGCGAGGAGCGGGGCTCTGGGCGGTTCCAGAACAG 3720 CTGCTACCCTTGGTGGGGTGGCTCCGGGGGAGGTATCGCAGCGGGGTCTCTGGCGCAGTT 3780 GCATCTCCGTATTGAGTGCGAAGGGAGGTGCCCCTATTATTATTTGACACCCCCCTTGTA 3840 TTTATGGAGGGGTGTTAAAGCCCGCGGCTGAGCTCGCCACTCCAGCCGGCGAGAGAAAGA 3900 AGAAAAGCTGGCAAAAGGAGTGTTGGACGGGGGCGGTACTGGGGGTGGGGACGGGGGCGG 3960 TGGAGAGGGAAGGTTGGGAGGGGCTGCGGTGCCGGCGGGGGTAGGAGAGCGGCTAGGGCG 4020 CGAGTGGGAACAGCCGCAGCGGAGGGGCCCCGGCGCGGAGCGGGGTTCACGCAGCCGCTA 4080 GCGCCCAGGCGCCTCTCGCCTTCTCCTTCAGGTGGCGCAAAACTTTGTGCCTTGGATTTT 4140 GGCAAATTGTTTTCCTCACCGCCACCTCCCGCGGCTTCTTAAGGGCGCCAGGGCCGATTT 4200 CGATTCCTCTGCCGCTGCGGGGCCGACTCCCGGGCTTTGCGCTCCGGGCTCCCGGGGGAG 4260 CGGGGGCTCGGCGGGCACCAAGCCGCTGGTTCACTAAGTGCGTCTCCGAGATAGCAGGGG 4320 ACTGTCCAAAGGGGGTGAAAGGGTGCTCCCTTTATTCCCCCACCAAGACCACCCAGCCGC 4380 TTTAGGGGATAGCTCTGCAAGGGGAGAGGTTCGGGACTGTGGCGCGCACTGCGCGCTGCG 4440 CCAGGTTTCCGCACCAAGACCCCTTTAACTCAAGACTGCCTCCCGCTTTGTGTGCCCCGC 4500 TCCAGCAGCCTCCCGCGACGATGCCCCTCAACGTTAGCTTCACCAACAGGAACTATGACC 4560 TCGACTACGACTCGGTGCAGCCGTATTTCTACTGCGACGAGGAGGAGAACTTCTACCAGC 4620 AGCAGCAGCAGAGCGAGCTGCAGCCCCCGGCGCCCAGCGAGGATATCTGGAAGAAATTCG 4680 AGCTGCTGCCCACCCCGCCCCTGTCCCCTAGCCGCCGCTCCGGGCTCTGCTCGCCCTCCT 4740 ACGTTGCGGTCACACCCTTCTCCCTTCGGGGAGACAACGACGGCGGTGGCGGGAGCTTCT 4800 CCACGGCCGACCAGCTGGAGATGGTGACCGAGCTGCTGGGAGGAGACATGGTGAACCAGA 4860 GTTTCATCTGCGACCCGGACGACGAGACCTTCATCAAAAACATCATCATCCAGGACTGTA 4920 TGTGGAGCGGCTTCTCGGCCGCCGCCAAGCTCGTCTCAGAGAAGCTGGCCTCCTACCAGG 4980 CTGCGCGCAAAGACAGCGGCAGCCCGAACCCCGCCCGCGGCCACAGCGTCTGCTCCACCT 5040 CCAGCTTGTACCTGCAGGATCTGAGCGCCGCCGCCTCAGAGTGCATCGACCCCTCGGTGG 5100 TCTTCCCCTACCCTCTCAACGACAGCAGCTCGCCCAAGTCCTGCGCCTCGCAAGACTCCA 5160 GCGCCTTCTCTCCGTCCTCGGATTCTCTGCTCTCCTCGACGGAGTCCTCCCCGCAGGGCA 5220 GCCCCGAGCCCCTGGTGCTCCATGAGGAGACACCGCCCACCACCAGCAGCGACTCTGGTA 5280 AGCGAAGCCCGCCCAGGCCTGTCAAAAGTGGGCGGCTGGATACCTTTCCCATTTTCATTG 5340 GCAGCTTATTTAACGGGCCACTCTTATTAGGAAGGAGAGATAGCAGATCTGGAGAGATTT 5400 GGGAGCTCATCACCTCTGAAACCTTGGGCTTTAGCGTTTCCTCCCATCCCTTCCCCTTAG 5460 ACTGCCCATGTTTGCAGCCCCCCTCCCCGTTTGTCTCCCACCCCTCAGGAATTTCATTTA 5520 GGTTTTTAAACCTTCTGGCTTATCTTACAACTCAATCCACTTCTTCTTACCTCCCGTTAA 5580 CATTTTAATTGCCCTGGGGCGGGGTGGCAGGGAGTGTATGAATGAGGATAAGAGAGGATT 5640 GATCTCTGAGAGTGAATGAATTGCTTCCCTCTTAACTTCCGAGAAGTGGTGGGATTTAAT 5700 GAACTATCTACAAAAATGAGGGGCTGTGTTTAGAGGCTAGGCAGGGCCTGCCTGAGTGCG 5760 GGAGCCAGTGAACTGCCTCAAGAGTGGGTGGGCTGAGGAGCTGGGATCTTCTCAGCCTAT 5820 TTTGAACACTGAAAAGCAAATCCTTGCCAAAGTTGGACTTTTTTTTTTCTTTTATTCCTT 5880 CCCCCGCCCTCTTGGACTTTTGGCAAAACTGCAATTTTTTTTTTTTTATTTTTCATTTCC 5940 AGTAAAATAGGGAGTTGCTAAAGTCATACCAAGCAATTTGCAGCTATCATTTGCAACACC 6000 TGAAGTGTTCTTGGTAAAGTCCCTCAAAAATAGGAGGTGCTTGGGAATGTGCTTTGCTTT 6060 GGGTGTGTCCAAAGCCTCATTAAGTCTTAGGTAAGAATTGGCATCAATGTCCTATCCTGG 6120 GAAGTTGCACTTTTCTTGTCCATGCCATAACCCAGCTGTCTTTCCCTTTATGAGACTCTT 6180 ACCTTCATGGTGAGAGGAGTAAGGGTGGCTGGCTAGATTGGTTCTTTTTTTTTTTTTTTC 6240 CTTTTTTAAGACGGAGTCTCACTCTGTCACTAGGCTGGAGTGCAGTGGCGCAATCAACCT 6300 CCAACCCCCTGGTTCAAGAGATTCTCCTGCCTCAGCCTCCCAAGTAGCTGGGACTACAGG 6360 TGCACACCACCATGCCAGGCTAATTTTTGTAATTTTAGTAGAGATGGGGTTTCATCGTGT 6420 TGGCCAGGATGGTCTCTCCTGACCTCACGATCCGCCCACCTCGGCCTCCCAAAGTGCTGG 6480 GATTACAGGTGTGAGCCAGGGCACCAGGCTTAGATGTGGCTCTTTGGGGAGATAATTTTG 6540 TCCAGAGACCTTTCTAACGTATTCATGCCTTGTATTTGTACAGCATTAATCTGGTAATTG 6600 ATTATTTTAATGTAACCTTGCTAAAGGAGTGATTTCTATTTCCTTTCTTAAAGAGGAGGA 6660 ACAAGAAGATGAGGAAGAAATCGATGTTGTTTCTGTGGAAAAGAGGCAGGCTCCTGGCAA 6720 AAGGTCAGAGTCTGGATCACCTTCTGCTGGAGGCCACAGCAAACCTCCTCACAGCCCACT 6780 GGTCCTCAAGAGGTGCCACGTCTCCACACATCAGCACAACTACGCAGCGCCTCCCTCCAC 6840 TCGGAAGGACTATCCTGCTGCCAAGAGGGTCAAGTTGGACAGTGTCAGAGTCCTGAGACA 6900 GATCAGCAACAACCGAAAATGCACCAGCCCCAGGTCCTCGGACACCGAGGAGAATGTCAA 6960 GAGGCGAACACACAACGTCTTGGAGCGCCAGAGGAGGAACGAGCTAAAACGGAGCTTTTT 7020 TGCCCTGCGTGACCAGATCCCGGAGTTGGAAAACAATGAAAAGGCCCCCAAGGTAGTTAT 7080 CCTTAAAAAAGCCACAGCATACATCCTGTCCGTCCAAGCAGAGGAGCAAAAGCTCATTTC 7140 TGAAGAGGACTTGTTGCGGAAACGACGAGAACAGTTGAAACACAAACTTGAACAGCTACG 7200 GAACTCTTGTGCGTAAGGAAAAGTAAGGAAAACGATTCCTTCTAACAGAAATGTCCTGAG 7260 CAATCACCTATGAACTTGTTTCAAATGCATGATCAAATGCAACCTCACAACCTTGGCTGA 7320 GTCTTGAGACTGAAAGATTTAGCCATAATGTAAACTGCCTCAAATTGGACTTTGGGCATA 7380 AAAGAACTTTTTTATGCTTACCATCTTTTTTTTTTCTTTAACAGATTTGTATTTAAGAAT 7440 TGTTTTTAAAAAATTTTAAGATTTACACAATGTTTCTCTGTAAATATTGCCATTAAATGT 7500 AAATAACTTTAATAAAACGTTTATAGCAGTTACACAGAATTTCAATCCTAGTATATAGTA 7560 CCTAGTATTATAGGTACTATAAACCCTAATTTTTTTTATTTAAGTACATTTTGCTTTTTA 7620 AAGTTGATTTTTTTCTATTGTTTTTAGAAAAAATAAAATAACTGGCAAATATATCATTGA 7680 GCCAAATCTTAAGTTGTGAATGTTTTGTTTCGTTTCTTCCCCCTCCCAACCACCACCATC 7740 CCTGTTTGTTTTCATCAATTGCCCCTTCAGAGGGCGGTCTTAAGAAAGGCAAGAGTTTTC 7800 CTCTGTTGAAATGGGTCTGGGGGCCTTAAGGTCTTTAAGTTCTTGGAGGTTCTAAGATGC 7860 TTCCTGGAGACTATGATAACAGCCAGAGTTGACAGTTAGAAGGAATGGCAGAAGGCAGGT 7920 GAGAAGGTGAGAGGTAGGCAAAGGAGATACAAGAGGTCAAAGGTAGCAGTTAAGTACACA 7980 AAGAGGCATAAGGACTGGGGAGTTGGGAGGAAGGTGAGGAAGAAACTCCTGTTACTTTAG 8040 TTAACCAGTGCCAGTCCCCTGCTCACTCCAAACCCAGGAATT8082 (2) INFORMATION FOR SEQ ID NO:42: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7011 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42: CGGGCCGCATCAGCCCTCCTCCTGTTTGCGCTCCCCAGCGTGCAATTTATTTGGGGGGCT 60 ACCGGGGATTGAACGGAGCGGGCGAGCGCTGCCAGGAGGTGGGGCCGGCCCCACCTGTCG 120 ACTGCCCGTAGTAGGCAGGGAGAGGGCGGGGTTTGTCCCATAGGGCCCGCCCCCCAGTCC 180 CTGGGTCCCGGGCGCGCGACGAGATATAAGGCAGTCAGGAAACAATGCGCCTGCAGCTCG 240 CGCTCCCGCGCCGATCCCGAGAGCGTCCGGGCCGCCGTGCGCGAGCGAGGGAGGGCGCGC 300 GCGCGGGGGGGGCGCGCTCGTGAGTGCGGGCCGCGCTCTCGGCGGCGCGCATGTGCGTGT 360 GTGCTGGCTGCCGGGCTGCCCCGAGCCGGCGGGGAGCCGGTCCGCTCCAGGTGGCGGGCG 420 GCTGGAGCGAGGTGAGGCTGCGGGTGGCCAGGGCACGGGCGCGGGTCCCGCGGTGCGGGC 480 TGGCTGCAGGCTGCCTTCTGGGCACGGCGCGCCCCCGCCCGGCCCCGCCGGGCCCTGGGA 540 GCTGCGCTCCGGGCGGCGCTGGCAAAGTTTGCTTTGAACTCGCTGCCCACAGTCGGGTCC 600 GCGCGCTGCGATTGGCTTCCCCTACCACTCTGACCCGGGGCCCGGCTTCCCGGGACGCGA 660 GGACTGGGCGCAGGCTGCAAGCTGGTGGGGTTGGGGAGGAACGAGAGCCCGGCAGCCGAC 720 TGTGCCGAGGGACCCGGGGACACCTCCTTCGCCCGGCCGGCACCCGGTCAGCACGTCCCC 780 CCTTCCCTCCCGCAGGGAGCGGACATGGACTACGACTCGTACCAGCACTATTTCTACGAC 840 TATGACTGCGGGGAGGATTTCTACCGCTCCACGGCGCCCAGCGAGGACATCTGGAAGAAA 900 TTCGAGCTGGTGCCATCGCCCCCCACGTCGCCGCCCTGGGGCTTGGGTCCCGGCGCAGGG 960 GACCCGGCCCCCGGGATTGGTCCCCCGGAGCCGTGGCCCGGAGGGTGCACCGGAGACGAA 1020 GCGGAATCCCGGGGCCACTCGAAAGGCTGGGGCAGGAACTACGCCTCCATCATACGCCGT 1080 GACTGCATGTGGAGCGGCTTCTCGGCCCGGGAACGGCTGGAGAGAGCTGTGAGCGACCGG 1140 CTCGCTCCTGGCGCGCCCCGGGGGAACCCGCCCAAGGCGTCCGCCGCCCCGGACTGCACT 1200 CCCAGCCTCGAAGCCGGCAACCCGGCGCCCGCCGCCCCCTGTCCGCTGGGCGAACCCAAG 1260 ACCCAGGCCTGCTCCGGGTCCGAGAGCCCAAGCGACTCGGGTAAGGACCTCCCCGAGCCA 1320 TCCAAGAGGGGGCCACCCCATGGGTGGCCAAAGCTCTGCCCCTGCCTGAGGTCAGGCATT 1380 GGCTCTTCTCAAGCTCTTGGGCCATCTCCGCCTCTCTTTGGCTGAAGCTGCCCGTGTAGT 1440 CCCCAACCGTGTCTGTCTGGCACGTGGGTGTGTTGGTAAACAGTTTGGAAAAGTGGCGTG 1500 GGAGCCAGCCTCCCTTTGATGATTATTGGAGCCCCAGGGGACAAGGGATTTGAGGTGAGG 1560 GTTGGCGCTTAGAGAGGACAATACTGGGGTTGGACTGTAAGGGATTGAAGGGGGTACCTT 1620 AAGAGACACTCCAAACCTGAAGTTTTTTTGCTGCTGCCTCTTTCCCTAGGAAACTCACAC 1680 TCCCCTAGGGGGAGAAGAAGCCGAGAGCCTTTTGTGCAAAGCCAAAACCTTCGTCCTTTT 1740 AAAAACCTAGGTCTCCAGTTGGCTTTACTTTAAAATGCCAATAATAAATGCCCTCTTCTC 1800 GTGCCTCCCCACCACCACTTACCACTCGTGCATCCCTGAGACAGGGAGGGAAGAATGAAC 1860 ACTCCCCATTAACAGATGGAAAAACTGAGGCTTAGAGATAGACAATCACTACAAGTCAGC 1920 TCCAGCTTTCTGCCATCTAGCCAGCCCCTCTTCCCCAATGCTCCATCCCAACCAGGCACC 1980 TCTTCCTTGATGTTTGGGGTCTTTGTGGTAGCTTATCTTAGAAGCACTACACCTTGCCTT 2040 GCTGTTTGTCCTGAGATGGAAAAGTGTCCTTCTTGCTCCCCCTCAATAGATCTCCAGCGT 2100 CAGCTGCTCCCTGGCATTCAACAAATATTCACTGGCCCCTACTTTGTGGCAATCTGTGGG 2160 CTACATGCTGGGGTCAAGGCAGTAGAACTCCAGGCCCTCCTCTCCCATCCTTGATGCAAG 2220 TGCAACCTCGCTGAGGGCAGACTGGGGCATCCTGTGCCACTAAACTACATTGTTCTTATT 2280 CTGGCATCTTAGACCTCCACACCCGTGAGAAATCCTGGAGAGGGTATTTTTGTAGAGTGT 2340 AGACTGTGGCTAGTGACAAATAAATTAGGACCAAGAAAGCTCACTGTAGCTTTTAGGAAT 2400 AACTTTTACACGACCATTTGATAGGGAACTGGGGAATGGGGTATGGAAGTTTTCCTACAC 2460 TTGAGAGAAAAAATAGGATAACAAAAATTAAAAGTCTTTTTTTCCTGGTCCACTGTGTTA 2520 AGGTCATTTTTAACCAGCTTGCTTTCTACACCAAGAGTTTATGTTTGTTTAATGGCTGGA 2580 AAGAGAATCTTGAGATCAAAAAACCAATAAAGATGTATCTCTACAACGGCTGGTGGAGTG 2640 GTAGAGTGGAAAGAGCATTGCTTTGGAAGTTGGAACATTTTAGTTTGAGATCCAGAACGT 2700 TACAAAGGTGATATGTGGACTTCGCTGATCTGGGCCTCAGTTTCCCCATTTGCACACGAT 2760 GGGGTTGGACTTGATTGTCCTGCTGATGACATTTCCTTGTCTGGATAGAGTAAGACACTA 2820 CTCTCTGAAAGGGAGAATGGTGTGCTTAAATTATTTCTTTCTTAGATAGAATCTTCCTGA 2880 GCCACGAGGCTTAACACTGAAAATTAAAGGTTTGGGATGTAGGAAAGCCTGCTGAATCAT 2940 TTTCTAACCTACCCTTTAACCTGAACCTGTTTGTGAGCTTCTAGTTCACTCACAGGCCAC 3000 ATGGCCTGGAACAAAATGCAACAGATTGCAAACAATGAGGCGGGGGGTGGGGAAAGTGAT 3060 TGGCAGCAGAGCTCACCCAATAGGGGCTAGGGGCTGGGTAAGACAGAATTCCAAACACAG 3120 CGTAATCAGCCAATCATGGGCTTTGGGGCCAGGAGGGCTGAATGGTCAGGTTTATTAATG 3180 GAGAAATAATGCGATTGTCCACACAATGGAAGCCTTCCTGACAAAGGGGCTCAAGCTTCC 3240 TGATATGCAAAGAAGCTGAGAACGGAGCTCTTCCTTTGCCGAGGCCGAGATCCATTAAGG 3300 TCGGACTTCTGTGTGGAGGCTGCAAAATGTGTGGAGCAGGAGGAGACTTTTCTCCCAATT 3360 GCCCCTCTCCTGGTTAGGTTAACCTAAGAGACCTTCAAGCCAGTGAATGAGAAGGGCGTG 3420 TCCAGGTGTCTCCAGGTCTCTGGTGTTATGAGCCCCATATCTGGGACATTCTGCTGCCCA 3480 GTCTCTGCCTCTGGTGCAGGTAGTTTGGAAATGGTCGCTTGTACCTTTGTGAAGTTCCTG 3540 CAGCTTCGCCGACCTATGATTACAAATCTAACCTTCTAGTCCAGGGAAGGAGGTGGGGCA 3600 GGCGACCTATAAATGATGGATGACTTTAGAAACCCATTGAACCCAGGAGCAAAATGCTCC 3660 TAAGGGAAACCCTTTCCCTCCCCTCTGTGGGTGAAGAGGGATGGGTTGTAGCCCTCCCTT 3720 CTCTGAATCTTCAGCTGAAAGGGATGGCAGAATAGAGAGGTGGGGGAATAATAGGATTTA 3780 TAACTTGTGAAAAGTAACAATTCCCCAAGTGCAGGCTGTGCTGGGCAGGAACAAAGGGCA 3840 GCTCTGCCCACAGACCCCTCATTTACAATTCTGATGGGGCATGAAAGAGCCCGACTGGGG 3900 AAGATCTTTATAGCTAAACTTTGTCCCAGGCCGGTAGCTCTTTCTCTCCAACCCCTCCGT 3960 GGGGGAGGGGAGAGCCTTTGCAGACTGGGGGCTGTTGGCTTGGGTCTGCCTTTTGTTCTT 4020 ATCTAAGCCTTGCTGTGCAAAAGGAAATTGGAGAATATTTTCCTTCTTGCTAATGTCCCC 4080 TCCTTTCCTTCACTGTGCCCTTACCACATTACAAATGAATCAGCTTTCTGCTCACCTCGA 4140 TTTGTATATATCTAAATTGGAAAAATGTCTCCTACCTTCCCAAGCACCAGCGTAGACAGC 4200 TAAAGCTGTAGGGTCTATGTTTGTGTTTCTCATGGGATGTGTTTCTTCTCTTGATCTCTT 4260 TTCTCGGACAGAGAATGAAGAAATTGATGTTGTGACAGTAGAGAAGAGGCAGTCTCTGGG 4320 TATTCGGAAGCCGGTCACCATCACGGTGCGAGCAGACCCCCTGGATCCCTGCATGAAGCA 4380 TTTCCACATCTCCATCCATCAGCAACAGCACAACTATGCTGCCCGTTTTCCTCCAGAAAG 4440 CTGCTCCCAAGAAGAGGCTTCAGAGAGGGGTCCCCAAGAAGAGGTTCTGGAGAGAGATGC 4500 TGCAGGGGAAAAGGAAGATGAGGAGGATGAAGAGATTGTGAGTCCCCCACCTGTAGAAAG 4560 TGAGGCTGCCCAGTCCTGCCACCCCAAACCTGTCAGTTCTGATACTGAGGATGTGACCAA 4620 GAGGAAGAATCACAACTTCCTGGAGCGCAAGAGGCGGAATGACCTGCGTTCGCGATTCTT 4680 GGCGCTGAGGGACCAGGTGCCCACCCTGGCCAGCTGCTCCAAGGCCCCCAAAGTAGTGAT 4740 CCTAAGCAAGGCCTTGGAATACTTGCAAGCCCTGGTGGGGGCTGAGAAGAGGATGGCTAC 4800 AGAGAAAAGACAGCTCCGATGCCGGCAGCAGCAGTTGCAGAAAAGAATTGCATACCTCAG 4860 TGGCTACTAACTGACCAAAAAGCCTGACAGTTCTGTCTTACGAAGACACAAGTTTATTTT 4920 TTAACCTCCCTCTCCCCTTTAGTAATTTGCACATTTTGGTTATGGTGGGACAGTCTGGAC 4980 AGTAGATCCCAGAATGCATTGCAGCCGGTGCACACACAATAAAGGCTTGCATTCTTGGAA 5040 ACCTTGAAACCCAGCTCTCCCTCTTCCCTGACTCATGGGAGTGCTGTATGTTCTCTGGCG 5100 CCTTTGGCTTCCCAGCAGGCAGCTGACTGAGGAGCCTTGGGGTCTGCCTAGCTCACTAGC 5160 TCTGAAGAAAAGGCTGACAGATGCTATGCAACAGGTGGTGGATGTTGTCAGGGGCTCCAG 5220 CCTGCATGAAATCTCACACTCTGCATGAGCTTTAGGCTAGGAAAGGATGCTCCCAACTGG 5280 TGTCTCTGGGGTGATGCAAGGACAGCTGGGCCTGGATGCTCTCCCTGAGGCTCCTTTTTC 5340 CAGAAGACACACGAGCTGTCTTGGGTGAAGACAAGCTTGCAGACTTGATCAACATTGACC 5400 ATTACCTCACTGTCAGACACTTTACAGTAGCCAAGGAGTTGGAAACCTTTATGTATTATG 5460 ATGTTAGCTGACCCCCTTCCTCCCACTCCCAATGCTGCGACCCTGGGAACACTTAAAAAG 5520 CTTGGCCTCTAGATTCTTTGTCTCAGAGCCCTCTGGGCTCTCTCCTCTGAGGGAGGGACC 5580 TTTCTTTCCTCACAAGGGACTTTTTTGTTCCATTATGCCTTGTTATGCAATGGGCTCTAC 5640 AGCACCCTTTCCCACAGGTCAGAAATATTTCCCCAAGACACAGGGAAATCGGTCCTAGCC 5700 TGGGGCCTGGGGATAGCTTGGAGTCCTGGCCCATGAACTTGATCCCTGCCCAGGTGTTTT 5760 CCGAGGGGCACTTGAGGCCCAGTCTTTTCTCAAGGCAGGTGTAAGACACTCAGAGGGAGA 5820 ACTGTACTGCTGCCTCTTTCCCACCTTCCTCATCTCAATCCTTGAGCGGCAAGTTTGAAG 5880 TTCTTCTGGAACCATGCAAATCTGTCCTCCTCATGCAATTCCAAGGAGCTTGCTGGCTCT 5940 GCAGCCACCTCTGGGCCCCTTCCAGCCTGCCATGAATCAGATATCTTTCCCAGAATCTGG 6000 GCGTTTCTGAAGTTTTGGGGAGAGCTGTTGGGACTCATCCAGTGCTCCAGAAGGTGGACT 6060 TGCTTCTGGGGGGTTTTAAAGGAGCCTCCAGGAGATATGCTTAGCCAACCATGATGGATT 6120 TTACCCCAGCTGGACTCGGCAGCTCCAAGTGGAATCCACGTGCAGCTTCTAGTCTGGGAA 6180 AGTCACCCAACCTAGCAGTTGTCATGTGGGTAACCTCAGGCACCTCTAAGCCTGTCCTGG 6240 AAGAAGGACCAGCAGCCCCTCCAGAACTCTGCCCAGGACAGCAGGTGCCTGCTGGCTCTG 6300 GGTTTGGAAGTTTGGGGTGGGTAGGGGGTGGTAAGTACTATATATGGCTCTGGAAAACCA 6360 GCTGCTACTTCCAAATCTATTGTCCATAATGGTTTCTTTCTGAGGTTGCTTCTTGGCCTC 6420 AGAGGACCCCAGGGGATGTTTGGAAATAGCCTCTCTACCCTTCTGGAGCATGGTTTACAA 6480 AAGCCAGCTGACTTCTGGAATTGTCTATGGAGGACAGTTTGGGTGTAGGTTACTGATGTC 6540 TCAACTGAATAGCTTGTGTTTTATAAGCTGCTGTTGGCTATTATGCTGGGGGAGTCTTTT 6600 TTTTTTATATTGTATTTTTGTATGCCTTTTGCAAAGTGGTGTTAACTGTTTTTGTACAAG 6660 GAAAAAAACTCTTGGGGCAATTTCCTGTTGCAAGGGTCTGATTTATTTTGAAAGGCAAGT 6720 TCACCTGAAATTTTGTATTTAGTTGTGATTACTGATTGCCTGATTTTAAAATGTTGCCTT 6780 CTGGGACATCTTCTAATAAAAGATTTCTCAAACATGTCAGAGTGGGGGCAGCTTATGCCA 6840 CCTGAGTCCTCCTCAACCACGGAAAACTATTTCAGGGTAGCCACAAGTGATCCAGAGGGC 6900 TGCACTTCTCTAACCATGTTGCTAACCTGGTCATTCCACTCTGGGTTCCTGAAATGCCAT 6960 TTCAGACATGTTGAAACAATGTAGGCTCAGTACTCAGTGAACACGGAATTC7011 (2) INFORMATION FOR SEQ ID NO:43: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1604 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43: GAATTCCGGGCGAGGGCCGGGCAGGAGGAGCGGGCGCGCGGCGGGCGAGGCTGGGACCCG 60 AGCGCGCTCACTTCGCCGCAAAGTGCCAACTTCCCCTGGAGTGCCGGGCGCGCACCGTCC 120 GGGCGCGGGGGAAAGAAAGGCAGCGGGAATTTGAGATTTTTGGGAAGAAAGTCGGATTTC 180 CCCCGTCCCCTTCCCCCTGTTACTAATCCTCATTAAAAAGAAAAACAACAATAACTGCAA 240 ACTTGCTACCATCCCGTACGTCCCCCACTCCTGGCACCATGAAGGCGGCCGTCGATCTCA 300 AGCCGACTCTCACCATCATCAAGACGGAAAAAGTCGATCTGGAGCTTTTCCCCTCCCCGG 360 ATATGGAATGTGCAGATGTCCCACTATTAACTCCAAGCAGCAAAGAAATGATGTCTCAAG 420 CATTAAAAGCTACTTTCAGTGGTTTCACTAAAGAACAGCAACGACTGGGGATCCCAAAAG 480 ACCCCCGGCAGTGGACAGAAACCCATGTTCGGGACTGGGTGATGTGGGCTGTGAATGAAT 540 TCAGCCTGAAAGGTGTAGACTTCCAGAAGTTCTGTATGAATGGAGCAGCCCTCTGCGCCC 600 TGGGTAAAGACTGCTTTCTCGAGCTGGCCCCAGACTTTGTTGGGGACATCTTATGGGAAC 660 ATCTAGAGATCCTGCAGAAAGAGGATGTGAAACCATATCAAGTTAATGGAGTCAACCCAG 720 CCTATCCAGAATCCCGCTATACCTCGGATTACTTCATTAGCTATGGTATTGAGCATGCCC 780 AGTGTGTTCCACCATCGGAGTTCTCAGAGCCCAGCTTCATCACAGAGTCCTATCAGACGC 840 TCCATCCCATCAGCTCGGAAGAGCTCCTCTCCCTCAAGTATGAGAATGACTACCCCTCGG 900 TCATTCTCCGAGACCCTCTCCAGACAGACACCTTGCAGAATGACTACTTTGCTATCAAAC 960 AAGAAGTCGTCACCCCAGACAACATGTGCATGGGGAGGACCAGTCGTGGTAAACTCGGGG 1020 GCCAGGACTCTTTTGAAAGCATAGAGAGCTACGATAGTTGTGATCGCCTCACCCAGTCCT 1080 GGAGCAGCCAGTCATCTTTCAACAGCCTGCAGCGTGTTCCCTCCTATGACAGCTTCGACT 1140 CAGAGGACTATCCGGCTGCCCTGCCCAACCACAAGCCCAAGGGCACCTTCAAGGACTATG 1200 TGCGGGACCGTGCTGACCTCAATAAGGACAAGCCTGTCATTCCTGCTGCTGCCCTAGCTG 1260 GCTACACAGGCAGTGGACCAATCCAGCTATGGCAGTTTCTTCTGGAATTACTCACTGATA 1320 AATCCTGTCAGTCTTTTATCAGCTGGACAGGAGATGGCTGGGAATTCAAACTTTCTGACC 1380 CAGATGAGGTGGCCAGGAGATGGGGAAAGAGGAAAAACAAACCTAAGATGAATTATGAGA 1440 AACTGAGCCGTGGCCTACGCTACTATTACGACAAAAACATCATCCACAAGACAGCGGGGA 1500 AACGCTACGTGTACCGCTTTGTGTGTGACCTGCAGAGCCTGCTGGGGTACACCCCTGAGG 1560 AGCTGCACGCCATGCTGGACGTCAAGCCAGATGCCGACGAGTGA1604 (2) INFORMATION FOR SEQ ID NO:44: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 3565 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44: GCAGCCGGGCGGCCGCAGAAGCGCCCAGGCCCGCGCGCCACCCCTCTGGCGCCACCGTGG 60 TTGAGCCCGTGACGTTTACACTCATTCATAAAACGCTTGTTATAAAAGCAGTGGCTGCGG 120 CGCCTCGTACTCCAACCGCATCTGCAGCGAGCAACTGAGAAGCCAAGACTGAGCCGGCGG 180 CCGCGGCGCAGCGAACGAGCAGTGACCGTGCTCCTACCCAGCTCTGCTTCACAGCGCCCA 240 CCTGTCTCCGCCCCTCGGCCCCTCGCCCGGCTTTGCCTAACCGCCACGATGATGTTCTCG 300 GGCTTCAACGCAGACTACGAGGCGTCATCCTCCCGCTGCAGCAGCGCGTCCCCGGCCGGG 360 GATAGCCTCTCTTACTACCACTCACCCGCAGACTCCTTCTCCAGCATGGGCTCGCCTGTC 420 AACGCGCAGGTAAGGCTGGCTTCCCGTCGCCGCGGGGCCGGGGGCTTGGGGTCGCGGAGG 480 AGGAGACACCGGGCGGGACGCTCCAGTAGATGAGTAGGGGGCTCCCTTGTGCCTGGAGGG 540 AGGCTGCCGTGGCCGGAGCGGTGCCGGCTCGGGGGCTCGGGACTTGCTCTGAGCGCACGC 600 ACGCTTGCCATAGTAAGAATTGGTTCCCCCTTCGGGAGGCAGGTTCGTTCTGAGCAACCT 660 CTGGTCTGCACTCCAGGACGGATCTCTGACATTAGCTGGAGCAGACGTGTCCCAAGCACA 720 AACTCGCTAACTAGAGCCTGGCTTCTTCGGGGAGGTGGCAGAAAGCGGCAATCCCCCCTC 780 CCCCGGCAGCCTGGAGCACGGAGGAGGGATGAGGGAGGAGGGTGCAGCGGGCGGGTGTGT 840 AAGGCAGTTTCATTGATAAAAAGCGAGTTCATTCTGGAGACTCCGGAGCGGCGCCTGCGT 900 CAGCGCAGACGTCAGGGATATTTATAACAAACCCCCTTTCAAGCAAGTGATGCTGAAGGG 960 ATAACGGGAACGCAGCGGCAGGATGGAAGAGACAGGCACTGCGCTGCGGAATGCCTGGGA 1020 GGAAAAGGGGGAGACCTTTCATCCAGGATGAGGGACATTTAAGATGAAATGTCCGTGGCA 1080 GGATCGTTTCTCTTCACTGCTGCATGCGGCACTGGGAACTCGCCCCACCTGTGTCCGGAA 1140 CCTGCTCGCTCACGTCGGCTTTCCCCTTCTGTTTTGTTCTAGGACTTCTGCACGGACCTG 1200 GCCGTCTCCAGTGCCAACTTCATTCCCACGGTCACTGCCATCTCGACCAGTCCGGACCTG 1260 CAGTGGCTGGTGCAGCCCGCCCTCGTCTCCTCTGTGGCCCCATCGCAGACCAGAGCCCCT 1320 CACCCTTTCGGAGTCCCCGCCCCCTCCGCTGGGGCTTACTCCAGGGCTGGCGTTGTGAAG 1380 ACCATGACAGGAGGCCGAGCGCAGAGCATTGGCAGGAGGGGCAAGGTGGAACAGGTGAGG 1440 AACTCTAGCGTACTCTTCCTGGGAATGTGGGGGCTGGGTGGGAAGCAGCCCCGGAGATGC 1500 AGGAGCCCAGTACAGAGGATGAAGCCACTGATGGGGCTGGCTGCACATCCGTAACTGGGA 1560 GCCCTGGCTCCAAGCCCATTCCATCCCAACTCAGACTCTGAGTCTCACCCTAAGAAGTAC 1620 TCTCATAGTTTCTTCCCTAAGTTTCTTACCGCATGCTTTCAGACTGGGCTCTTCTTTGTT 1680 CTCTTGCTGAGGATCTTATTTTAAATGCAAGTCACACCTATTCTGCAACTGCAGGTCAGA 1740 AATGGTTTCACAGTGGGGTGCCAGGAAGCAGGGAAGCTGCAGGAGCCAGTTCTACTGGGG 1800 TGGGTGAATGGAGGTGATGGCAGACACTTTTACTGAATGTCGGTCTTTTTTTGTGATTAT 1860 TCTAGTTATCTCCAGAAGAAGAAGAGAAAAGGAGAATCCGAAGGGAAAGGAATAAGATGG 1920 CTGCAGCCAAATGCCGCAACCGGAGGAGGGAGCTGACTGATACACTCCAAGCGGTAGGTA 1980 CTCTGTGGGTTGCTCCTTTTTAAAACTTAAGGGAAAGTTGGAGATTGAGCATAAGGGCCC 2040 TTGAGTAAGACTGTGTCTTATGCTTTCCTTTATCCCTCTGTATACAGGAGACAGACCAAC 2100 TAGAAGATGAGAAGTCTGCTTTGCAGACCGAGATTGCCAACCTGCTGAAGGAGAAGGAAA 2160 AACTAGAGTTCATCCTGGCAGCTCACCGACCTGCCTGCAAGATCCCTGATGACCTGGGCT 2220 TCCCAGAAGAGATGTCTGTGGCTTCCCTTGATCTGACTGGGGGCCTGCCAGAGGTTGCCA 2280 CCCCGGAGTCTGAGGAGGCCTTCACCCTGCCTCTCCTCAATGACCCTGAGCCCAAGCCCT 2340 CAGTGGAACCTGTCAAGAGCATCAGCAGCATGGAGCTGAAGACCGAGCCCTTTGATGACT 2400 TCCTGTTCCCAGCATCATCCAGGCCCAGTGGCTCTGAGACAGCCCGCTCCGTGCCAGACA 2460 TGGACCTATCTGGGTCCTTCTATGCAGCAGACTGGGAGCCTCTGCACAGTGGCTCCCTGG 2520 GGATGGGGCCCATGGCCACAGAGCTGGAGCCCCTGTGCACTCCGGTGGTCACCTGTACTC 2580 CCAGCTGCACTGCTTACACGTCTTCCTTCGTCTTCACCTACCCCGAGGCTGACTCCTTCC 2640 CCAGCTGTGCAGCTGCCCACCGCAAGGGCAGCAGCAGCAATGAGCCTTCCTCTGACTCGC 2700 TCAGCTCACCCACGCTGCTGGCCCTGTGAGGGGGCAGGGAAGGGGAGGCAGCCGGCACCC 2760 ACAAGTGCCACTGCCCGAGCTGGTGCATTACAGAGAGGAGAAACACATCTTCCCTAGAGG 2820 GTTCCTGTAGACCTAGGGAGGACCTTATCTGTGCGTGAAACACACCAGGCTGTGGGCCTC 2880 AAGGACTTGAAAGCATCCATGTGTGGACTCAAGTCCTTACCTCTTCCGGAGATGTAGCAA 2940 AACGCATGGAGTGTGTATTGTTCCCAGTGACACTTCAGAGAGCTGGTAGTTAGTAGCATG 3000 TTGAGCCAGGCCTGGGTCTGTGTCTCTTTTCTCTTTCTCCTTAGTCTTCTCATAGCATTA 3060 ACTAATCTATTGGGTTCATTATTGGAATTAACCTGGTGCTGGATATTTTCAAATTGTATC 3120 TAGTGCAGCTGATTTTAACAATAACTACTGTGTTCCTGGCAATAGTGTGTTCTGATTAGA 3180 AATGACCAATATTATACTAAGAAAAGATACGACTTTATTTTCTGGTAGATAGAAATAAAT 3240 AGCTATATCCATGTACTGTAGTTTTTCTTCAACATCAATGTTCATTGTAATGTTACTGAT 3300 CATGCATTGTTGAGGTGGTCTGAATGTTCTGACATTAACAGTTTTCCATGAAAACGTTTT 3360 ATTGTGTTTTTAATTTATTTATTAAGATGGATTCTCAGATATTTATATTTTTATTTTATT 3420 TTTTTCTACCTTGAGGTCTTTTGACATGTGGAAAGTGAATTTGAATGAAAAATTTAAGCA 3480 TTGTTTGCTTATTGTTCCAAGACATTGTCAATAAAAGCATTTAAGTTGAATGCGACCAAC 3540 CTTGTGCTCTTTTCATTCTGGAAGT3565 (2) INFORMATION FOR SEQ ID NO:45: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 3225 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:45: GGCGGCAGCGCCCTGCCGACGCCGGGGAGGGACGCAGGCAGGCGGCGGGCAGCGGGAGGC 60 GGCACCCCGGTGCTCCCCGCGGCTCTCGGCGGAGCCCCGCCGCCCGCCGCGCCATGGCCC 120 GAAGACCCCGGCACAGCATATATAGCAGTGACGAGGATGATGAGGACTTTGAGATGTGTG 180 ACCATGACTATGATGGGCTGCTTCCCAAGTCTGGAAAGCGTCACTTGGGGAAAACAAGGT 240 GGACCCGGGAAGAGGATGAAAAACTGAAGAAGCTGGTGGAACAGAATGGAACAGATGACT 300 GGAAAGTTATTGCCAATTATCTCCCGAATCGAACAGATGTGCAGTGCCAGCACCGATGGC 360 AGAAAGTACTAAACCCTGAGCTCATCAAGGGTCCTTGGACCAAAGAAGAAGATCAGAGAG 420 TGATAGAGCTTGTACAGAAATACGGTCCGAAACGTTGGTCTGTTATTGCCAAGCACTTAA 480 AGGGGAGAATTGGAAAACAATGTAGGGAGAGGTGGCATAACCACTTGAATCCAGAAGTTA 540 AGAAAACCTCCTGGACAGAAGAGGAAGACAGAATTATTTACCAGGCACACAAGAGACTGG 600 GGAACAGATGGGCAGAAATCGCAAAGCTACTGCCTGGACGAACTGATAATGCTATCAAGA 660 ACCACTGGAATTCTACAATGCGTCGGAAGGTCGAACAGGAAGGTTATCTGCAGGAGTCTT 720 CAAAAGCCAGCCAGCCAGCAGTGGCCACAAGCTTCCAGAAGAACAGTCATTTGATGGGTT 780 TTGCTCAGGCTCCGCCTACAGCTCAACTCCCTGCCACTGGCCAGCCCACTGTTAACAACG 840 ACTATTCCTATTACCACATTTCTGAAGCACAAAATGTCTCCAGTCATGTTCCATACCCTG 900 TAGCGTTACATGTAAATATAGTCAATGTCCCTCAGCCAGCTGCCGCAGCCATTCAGAGAC 960 ACTATAATGATGAAGACCCTGAGAAGGAAAAGCGAATAAAGGAATTAGAATTGCTCCTAA 1020 TGTCAACCGAGAATGAGCTAAAAGGACAGCAGGTGCTACCAACACAGAACCACACATGCA 1080 GCTACCCCGGGTGGCACAGCACCACCATTGCCGACCACACCAGACCTCATGGAGACAGTG 1140 CACCTGTTTCCTGTTTGGGAGAACACCACTCCACTCCATCTCTGCCAGCGGATCCTGGCT 1200 CCCTACCTGAAGAAAGCGCCTCGCCAGCAAGGTGCATGATCGTCCACCAGGGCACCATTC 1260 TGGATAATGTTAAGAACCTCTTAGAATTTGCAGAAACACTCCAATTTATAGATTCTTTCT 1320 TAAACACTTCCAGTAACCATGAAAACTCAGACTTGGAAATGCCTTCTTTAACTTCCACCC 1380 CCCTCATTGGTCACAAATTGACTGTTACAACACCATTTCATAGAGACCAGACTGTGAAAA 1440 CTCAAAAGGAAAATACTGTTTTTAGAACCCCAGCTATCAAAAGGTCAATCTTAGAAAGCT 1500 CTCCAAGAACTCCTACACCATTCAAACATGCACTTGCAGCTCAAGAAATTAAATACGGTC 1560 CCCTGAAGATGCTACCTCAGACACCCTCTCATCTAGTAGAAGATCTGCAGGATGTGATCA 1620 AACAGGAATCTGATGAATCTGGATTTGTTGCTGAGTTTCAAGAAAATGGACCACCCTTAC 1680 TGAAGAAAATCAAACAAGAGGTGGAATCTCCAACTGATAAATCAGGAAACTTCTTCTGCT 1740 CACACCACTGGGAAGGGGACAGTCTGAATACCCAACTGTTCACGCAGACCTCGCCTGTGC 1800 GAGATGCACCGAATATTCTTACAAGCTCCGTTTTAATGGCACCAGCATCAGAAGATGAAG 1860 ACAATGTTCTCAAAGCATTTACAGTACCTAAAAACAGGTCCCTGGCGAGCCCCTTGCAGC 1920 CTTGTAGCAGTACCTGGGAACCTGCATCCTGTGGAAAGATGGAGGAGCAGATGACATCTT 1980 CCAGTCAAGCTCGTAAATACGTGAATGCATTCTCAGCCCGGACGCTGGTCATGTGAGACA 2040 TTTCCAGAAAAGCATTATGGTTTTCAGAACAGTTCAAGTTGACTTGGGATATATCATTCC 2100 TCAACATGAAACTTTTCATGAATGGGAGAAGAACCTATTTTTGTTGTGGTACAACAGTTG 2160 AGAGCACGACCAAGTGCATTTAGTTGAATGAAGTCTTCTTGGATTTCACCCAACTAAAAG 2220 GATTTTTAAAAATAAATAACAGTCTTACCTAAATTATTAGGTAATGAATTGTAGCCAGTT 2280 GTTAATATCTTAATGCAGATTTTTTTAAAAAAAAACATAAAATGATTTATCTGGTATTTT 2340 AAAGGATCCAACAGATCAGTATTTTTTCCTGTGATGGGTTTTTTGAAATTTGACACATTA 2400 AAAGGTACTCCAGTATTTCACTTTTCTCGATCACTAAACATATGCATATATTTTTAAAAA 2460 TCAGTAAAAGCATTACTCTAAGTGTAGACTTAATACCATGTGACATTTAATCCAGATTGT 2520 AAATGCTCATTTATGGTTAATGACATTGAAGGTACATTTATTGTACCAAACCATTTTATG 2580 AGTTTTCTGTTAGCTTGCTTTAAAAATTATTACTGTAAGAAATAGTTTTATAAAAAATTA 2640 TATTTTTATTCAGTAATTTAATTTTGTAAATGCCAAATGAAAAACGTTTTTTGCTGCTAT 2700 GGTCTTAGCCTGTAGACATGCTGCTAGTATCAGAGGGGCAGTAGAGCTTGGACAGAAAGA 2760 AAAGAAACTTGGTGTTAGGTAATTGACTATGCACTAGTATTTCAGACTTTTTAATTTTAT 2820 ATATATATACATTTTTTTTCCTTCTGCAATACATTTGAAAACTTGTTTGGGAGACTCTGC 2880 ATTTTTTATTGTGGTTTTTTTGTTATTGTTGGTTTATACAAGCATGCGTTGCACTTCTTT 2940 TTTGGGAGATGTGTGTTGTTCATGTTCTATGTTTTGTTTTGTGTGTAGCCTGACTGTTTT 3000 ATAATTTGGGAGTTCTCGATTTGATCCGCATCCCCTGTGGTTTCTAAGTGTATGGTCTCA 3060 GAACTGTTGCATGGATCCTGTGTTTGCAACTGGGGAGACAGAAACTGTGGTTGATAGCCA 3120 GTCACTGCCTTAAGAACATTTGATGCAAGATGGCCAGCACTGAACTTTTGAGATATGACG 3180 GTGTACTTACTGCCTTGTAGCAAAATAAAGATGTGCCCTTATTTT3225 (2) INFORMATION FOR SEQ ID NO:46: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2638 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46: GCTGACGCCTTCGAGCGCGGCCCGGGGCCCGGAGCGGCCGGAGCAGCCCGGGTCCTGACC 60 CCGGCCCGGCTCCCGCTCCGGGCTCTGCCGGCGGGCGGGCGAGCGCGGCGCGGTCCGGGC 120 CGGGGGGATGTCTCGGCGGACGCGCTGCGAGGATCTGGATGAGCTGCACTACCAGGACAC 180 AGATTCAGATGTGCCGGAGCAGAGGGATAGCAAGTGCAAGGTCAAATGGACCCATGAGGA 240 GGACGAGCAGCTGAGGGCCCTGGTGAGGCAGTTTGGACAGCAGGACTGGAAGTTCCTGGC 300 CAGCCACTTCCCTAACCGCACTGACCAGCAATGCCAGTACAGGTGGCTGAGAGTTTTGAA 360 TCCAGACCTTGTCAAGGGGCCATGGACCAAAGAGGAAGACCAAAAAGTCATCGAGCTGGT 420 TAAGAAGTATGGCACAAAGCAGTGGACACTGATTGCCAAGCACCTGAAGGGCCGGCTGGG 480 GAAGCAGTGCCGTGAACGCTGGCACAACCACCTCAACCCTGAGGTGAAGAAGTCTTGCTG 540 GACCGAGGAGGAGGACCGCATCATCTGCGAGGCCCACAAGGTGCTGGGCAACCGCTGGGC 600 CGAGATCGCCAAGATGTTGCCAGGGAGGACAGACAATGCTGTGAAGAATCACTGGAACTC 660 TACCATCAAAAGGAAGGTGGACACAGGAGGCTTCTTGAGCGAGTCCAAAGACTGCAAGCC 720 CCCAGTGTACTTGCTGCTGGAGCTCGAGGACAAGGACGGCCTCCAGAGTGCCCAGCCCAC 780 GGAAGGCCAGGGAAGTCTTCTGACCAACTGGCCCTCCGTCCCTCCTACCATAAAGGAGGA 840 GGAAAACAGTGAGGAGGAACTTGCAGCAGCCACCACATCGAAGGAACAGGAGCCCATCGG 900 TACAGATCTGGACGCAGTGCGAACACCAGAGCCCTTGGAGGAATTCCCGAAGCGTGAGGA 960 CCAGGAAGGCTCCCCACCAGAAACGAGCCTGCCTTACAAGTGGGTGGTGGAGGCAGCTAA 1020 CCTCCTCATCCCCGCTGTGGGTTCTAGCCTCTCTGAAGCCCTGGACTTGATCGAGTCGGA 1080 CCCTGATGCTTGGTGTGACCTGAGTAAATTTGACCTCCCTGAGGAACCATCTGCAGAGGA 1140 CAGTATCAACAACAGCCTAGTGCAGCTGCAAGCGTCACATCAGCAGCAAGTCCTGCCACC 1200 CCGCCAGCCTTCCGCCCTGGTGCCCAGTGTGACCGAGTACCGCCTGGATGGCCACACCAT 1260 CTCAGACCTGAGCCGGAGCAGCCGGGGCGAGCTGATCCCCATCTCCCCCAGCACTGAAGT 1320 CGGGGGCTCTGGCATTGGCACACCGCCCTCTGTGCTCAAGCGGCAGAGGAAGAGGCGTGT 1380 GGCTCTGTCCCCTGTCACTGAGAATAGCACCAGTCTGTCCTTCCTGGATTCCTGTAACAG 1440 CCTCACGCCCAAGAGCACACCTGTTAAGACCCTGCCCTTCTCGCCCTCCCAGTTTCTGAA 1500 CTTCTGGAACAAACAGGACACATTGGAGCTGGAGAGCCCCTCGCTGACATCCACCCCAGT 1560 GTGCAGCCAGAAGGTGGTGGTCACCACACCACTGCACCGGGACAAGACACCCCTGCACCA 1620 GAAACATGCTGCGTTTGTAACCCCAGATCAGAAGTACTCCATGGACAACACTCCCCACAC 1680 GCCAACCCCGTTCAAGAACGCCCTGGAGAAGTACGGACCCCTGAAGCCCCTGCCACAGAC 1740 CCCGCACCTGGAGGAGGACTTGAAGGAGGTGCTGCGTTCTGAGGCTGGCATCGAACTCAT 1800 CATCGAGGACGACATCAGGCCCGAGAAGCAGAAGAGGAAGCCTGGGCTGCGGCGGAGCCC 1860 CATCAAGAAAGTCCGGAAGTCTCTGGCTCTTGACATTGTGGATGAGGATGTGAAGCTGAT 1920 GATGTCCACACTGCCCAAGTCTCTATCCTTGCCGACAACTGCCCCTTCAAACTCTTCCAG 1980 CCTCACCCTGTCAGGTATCAAAGAAGACAACAGCTTGCTCAACCAGGGCTTCTTGCAGGC 2040 CAAGCCCGAGAAGGCAGCAGTGGCCCAGAAGCCCCGAAGCCACTTCACGACACCTGCCCC 2100 TATGTCCAGTGCCTGGAAGACGGTGGCCTGCGGGGGGACCAGGGACCAGCTTTTCATGCA 2160 GGAGAAAGCCCGGCAGCTCCTGGGCCGCCTGAAGCCCAGCCACACATCTCGGACCCTCAT 2220 CTTGTCCTGAGGTGTTGAGGGTGTCACGAGCCCATTCTCATGTTTACAGGGGTTGTGGGG 2280 GCAGAGGGGGTCTGTGAATCTGAGAGTCATTCAGGTGACCTCCTGCAGGGAGCCTTCTGC 2340 CACCAGCCCCTCCCCAGACTCTCAGGTGGAGGCAACAGGGCCATGTGCTGCCCTGTTGCC 2400 GAGCCCAGCTGTGGGCGGCTCCTGGTGCTAACAACAAAGTTCCACTTCCAGGTCTGCCTG 2460 GTTCCCTCCCCAAGGCCACAGGGAGCTCCGTCAGCTTCTCCCAAGCCCACGTCAGGCCTG 2520 GCCTCATCTCAGACCCTGCTTAGGATGGGGGATGTGGCCAGGGGTGCTCCTGTGCTCACC 2580 CTCTCTTGGTGCATTTTTTTGGAAGAATAAAATTGCCTCTCTCTTTGAAAAAAAAAAA26 38 (2) INFORMATION FOR SEQ ID NO:47: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 790 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:47: AGAATTTAGAAGCAGGGAGATGTAATTAGAGAATATGTCATTACCTAGAAATGAAGCCAC 60 AAAGTCTAAAGTAAAGCAGTTAGAAAGGAAGTGGACAGATAAATAGATGATTAATGTATT 120 TAGTGTCATTTATCTATACACTAAAACTTTTATTCTGTGAATGCTTTTCCTCAAATTCTT 180 CCCTGCAAAAAGAAATAAAATATTACTAAGGTAGCAACTCATTTTTTTGAAAATCCTTTA 240 TATTTAGGTGCTCCAAATACTGCAGAATTAAGGATTTGTCGTGTAAACAAGAATTGTGGA 300 AGTGTCAGAGGAGGAGATGAAATATTTCTACTTTGTGACAAAGTTCAGAAAGGTATTTAT 360 TTATTTCATTGAATTTAGAATAAATTTTAGATTAATAGATGCAGTTACTTTGTTTTCCCA 420 TTTTTTTTTTTTTGGTTTCTTATTGACTAGATGACATAGAAGTTCGTTTTGTGTTGAACG 480 ATTGGGAAGCAAAAGGCATCTTTTCACAAGCTGATGTACACCGTCAAGTAGCCATTGTTT 540 TCAAAACTCCACCATATTGCAAAGCTATCACAGAACCCGTAACAGTAAAAATGCAGTTGC 600 GGAGACCTTCTGACCAGGAAGTTAGTGAATCTATGGATTTTAGATATCTGCCAGATGAAA 660 AAGGTATGACATTTTGCTGGTAATAATTTATATATTTCTTGAAGTGGTCCTGCTAATAAC 720 ATCTTCTTGTAATATTCATTTGAGTACAGTTATGTATATTCATAATTTATGTTTCTTTTC 780 CTGGAAGCTT790 (2) INFORMATION FOR SEQ ID NO:48: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2757 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:48: CTAGGCTTTTGCAAAAAGCTTCACGCTGCCGCAAGCACTCAGGGCGCAAGGGCTGCTAAA 60 GGAAGCGGAACACGTAGAAAGCCAGTCCGCAGAAACGGTGCTGACCCCGGATGAATGTCA 120 GCTACTGGGCTATCTGGACAAGGGAAAACGCAAGCGCAAAGAGAAAGCAGTTCCTGTGCC 180 TTAAGAACATTAGAACCTTCCTGTCCACCTGCTGTGAGAAGTTCGGCCTCAAGCGGAGCG 240 AGCTCTTCGAAGCCTTTGACCTCTTCGATGTGCAGGATTTTGGCAAGGTCATCTACACCC 300 TGTCTGCTCTGTCCTGGACCCCGATCGCCCAGAACAGGGGGATCATGCCCTTCCCCACCG 360 AGGAGGAGAGTGTAGGTGATGAAGACATCTACAGTGGCCTGTCCGACCAGATCGACGACA 420 CGGTGGAGGAGGATGAGGACCTGTATGACTGCGTGGAGAATGAGGAGGCGGAAGGCGACG 480 AGATCTATGAGGACCTCATGCGCTCGGAGCCCGTGTCCATGCCGCCCAAGATGACAGAGT 540 ATGACAAGCGCTGCTGCTGCCTGCGGGAGATCCAGCAGACGGAGGAGAAGTACACTGACA 600 CGCTGGGCTCCATCCAGCAGCATTTCTTGAAGCCCCTGCAACGGTTCCTGAAACCTCAAG 660 ACATTGAGATCATCTTTATCAACATTGAGGACCTGCTTCGTGTTCATACTCACTTCCTAA 720 AGGAGATGAAGGAAGCCCTGGGCACCCCTGGCGCACCGAATCTCTACCAGGTCTTCATCA 780 AATACAAGGAGAGGTTCCTCGTCTATGGCCGCTACTGCAGCCAGGTGGAGTCAGCCAGCA 840 AACACCTGGACCGTGTGGCCGCAGCCCGGGAGGACGTGCAGATGAAGCTGGAGGAATGTT 900 CTCAGAGAGCCAACAACGGGAGGTTCACTGCGCGACCTGCTGATGGTGCCTATGCAGCGA 960 GTTCTCAAATATCACCTCCTTCTCCAGGAGCTGGTGAAACACACGCAGGAGGCGATGGAG 1020 CAAGGAAACTGCGGCTGGCCCTGGATGCCATGAGGGACCTGGCTCAGTGCGTGAACGAGG 1080 TCAAGCGAGACAACGAGACACTGCGACAGATCACCAATTTCCAGCTGTCCATTGAGAACC 1140 TGGACCAGTCTCTGGCTCACTATGGCCGGCCCAAGATCGACGGGGAACTCAAGATCACCT 1200 CGGTGGAACGGCGCTCCAAGATGGACAGGTATGCCTTCCTGCTCGACAAAGCTCTACTCA 1260 TCTGTAAGCGCAGGGGAGACTCCTATGACCTCAAGGACTTTGTAAACCTGCACAGCTTCC 1320 AGGTTCGGGATGACTCTTCAGGAGACCGAGACAACAAGAAGTGGAGCCACATGTTCCTCC 1380 TGATCGAGGACCAAGGTGCCCAGGGCTATGAGCTGTTCTTCAAGACAAGAGAATTGAAGA 1440 AGAAGTGGATGGAGCAGTTTGAGATGGCCATCTCCAACATCTATCCGGAGAATGCCACCG 1500 CCAACGGGCATGACTTCCAGATGTTCTCCTTTGAGGAGACCACATCCTGCAAGGCCTGTC 1560 AGATGCTGCTTAGAGGTACCTTCTATCAGGGCTACCGCTGCCATCGGTGCCGGGCATCTG 1620 CACACAAGGAGTGTCTGGGGAGGGTCCCTCCATGTGGCCGACATGGGCAAGATTTCCCAG 1680 GAACTATGAAGAAGGACAAACTACATCGCAGGGCTCAGGACAAAAAGAGGAATGAGCTGG 1740 GTCTGCCCAAGATGGAGGTGTTTCAGGAATACTACGGGCTTCCTCCACCCCCTGGAGCCA 1800 TTGGACCCTTTCTACGGCTCAACCCTGGAGACATTGTGGAGCTCACGAAGGCTGAGGCTG 1860 AACAGAACTGGTGGGAGGGCAGAAATACATCTACTAATGAAATTGGCTGGTTTCCTTGTA 1920 ACAGGGTGAAGCCCTATGTCCATGGCCCTCCTCAGGACCTGTCTGTTCATCTCTGGTACG 1980 CAGGCCCCATGGAGCGGGCAGGGGCAGAGAGCATCCTGGCCAACCGCTCGGACGGGACTT 2040 TCTTGGTGCGGCAGAGGGTGAAGGATGCAGCAGAATTTGCCATCAGCATTAAATATAACG 2100 TCGAGGTCAAGCACACGGTTAAAATCATGACAGCAGAAGGACTGTACCGGATCACAGAGA 2160 AAAAGGCTTTCCGGGGGCTTACGGAGCTGGTGGAGTTTTACCAGCAGAACTCTCTAAAGG 2220 ATTGCTTCAAGTCTCTGGACACCACCTTGCAGTTCCCCTTCAAGGAGCCTGAAAAGAGAA 2280 CCATCAGCAGGCCAGCAGTGGGAAGCACAAAGTATTTTGGCACAGCCAAAGCCCGCTATG 2340 ACTTCTGCGCCCGTGACCGTTCAGAGCTGTCGCTCAAGGAGGGTGACATCATCAAGATCC 2400 TTAACAAGAAGGGACAGCAAGGCTGGTGGCGAGGGGAGATCTATGGCCGGGTTGGCTGGT 2460 TCCCTGCCAACTACGTGGAGGAAGATTATTCTGAATACTGCTGAGCCCTGGTGCCTTGGC 2520 AGAGAGACGAGAAACTCCAGGCTCTGAGCCCGGCGTGGCGAGGCAGCGGACCAGGGGCTG 2580 TGACAGCTCCGGCGGGTGGAGACTTTGGGATGGACTGGAGGAGGCCAGCGTCCAGCTGGC 2640 GGTGCTCCCGGGATGTGCCCTGACATGGTTAATTTATAACACCCCGATTTTCCTCTTGGG 2700 TCCCCTCAAGCAGACGGGGGCTCAAGGGGGTTACATTTAATAAAAGGATGAAGATGG275 7 (2) INFORMATION FOR SEQ ID NO:49: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4175 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49: TCCTCGTCGTCTGTGGATTGCTAAACCTGAGTGGGAAGGGGGGGGAAAAAAAAAAGGGTG 60 GGTTGTTGTTTTGTTTAAAAAAAGAAAAAATCCCTTAAGTGGATTTGTACCAGCGTGGAA 120 GATAACTGGGGATTTTTGTTGTTTGTTTTGGGAATAGAAACTAAAAAATGGAGACTGTAA 180 GTAGAAGCAGCTTCCAGCCTCATCCAGGACTGCAGAAGACCTTGGAACAGTTTCATCTGA 240 GCTCTATGAGCTCCCTGGGTGGCCCTGCTGCTTTCTCAGCGCGATGGGCACAGGAGATGT 300 ACAAGAAAGACAATGGCAAAGACCCAGCGGAACCTGTACTGCATCTGCCCCCTATCCAGC 360 CCCCCCCGGTGATGCCTGGTCCCTTCTTCATGCCCTCGGACAGATCCACTGAGAGGTGCG 420 AGACCATCCTGGAAGGGGAAACCATCTCCTGCTTCGTGGTGGGTGGGGAAAAGCGCCTTT 480 GCTTGCCCCAGATCCTGAACTCGGTGCTCAGGGACTTCTCCCTGCAGCAGATCAATTCGG 540 TGTGCGATGAGCTACACATTTACTGCTCCAGATGCACCGCTGACCAGCTGGAGATCCTCA 600 AAGTCATGGGCATCTTGCCCTTCTCTGCCCCCTCCTGCGGGCTGATCACTAAAACTGATG 660 CTGAGAGGCTTTGCAATGCCTTGCTTTATGGTGGCACCTATCCTCCCCACTGCAAGAAGG 720 AATTCTCTAGCACGATTGAGCTGGAGCTTACAGAGAAGAGCTTCAAGGTGTACCACGAGT 780 GCTTTGGGAAGTGTAAGGGACTCCTGGTACCAGAGCTTTACAGTAACCCCAGCGCAGCCT 840 GCATCCAGTGCTTGGACTGCAGGCTCATGTACCCGCCTCACAAATTTGTGGTCCACTCTC 900 ACAAATCCCTGGAAAACAGGACTTGCCACTGGGGCTTTGACTCTGCAAACTGGAGGTCCT 960 ACATCCTCCTTAGCCAGGATTACACTGGGAAAGAGGAGAAAGCTAGGCTGGGCCAGCTCT 1020 TAGATGAAATGAAAGAAAAATTTGACTATAACAACAAATACAAGAGGAAAGCCCCCAGGA 1080 ACCGTGAGTCTCCTAGAGTTCAGCTCCGCCGGACCAAAATGTTCAAGACAATGCTGTGGG 1140 ATCCAGCTGGAGGTTCAGCGGTACTGCAGCGTCAGCCAGATGGAAATGAGGTCCCTTCAG 1200 ATCCTCCTGCTTCCAAGAAAACCAAAATAGACGACTCCGCTTCCCAATCTCCAGCTTCTA 1260 CTGAGAAGGAAAAGCAGTCCAGTTGGTTACGGTCCTTATCCAGTTCATCTAATAAGAGCA 1320 TTGGCTGTGTCCATCCCCGTCAGCGTCTCTCAGCTTTCCGGCCCTGGTCCCCTGCTGTAT 1380 CAGCAAATGAGAAAGAGCTCTCAACCCATCTTCCTGCATTGATCCGAGACAGCAGTTTTT 1440 ACTCCTACAAAAGCTTTGAGAATGCTGTGGCCCCCAACGTGGCACTCGCACCTCCTGCCC 1500 AACAGAAAGTTGTGAGCAACCCACCCTGTGCCACAGTGGTGTCCCGGAGCAGCGAACCGC 1560 CGAGCAGCGCTGCGCAGCCACGGAAAAGAAAACATGCTGCAGAAACCCCGGCTGTCCCAG 1620 AGCCAGTGGCCACGGTTACTGCCCCTGAAGAGGATAAGGAATCAGAAGCAGAAATTGAAG 1680 TAGAGACCAGGGAGGAATTCACCTCCTCCTTATCCTCGCTCTCCTCCCCATCCTTTACTT 1740 CATCCAGCTCTGCAAAGGACATGAGCTCACCTGGGATGCAAGCCCCAGTCCCAGTCAACA 1800 GTTCATATGAGGTTGCAGCACATTCTGACTCTCACAGCAGTGGGTTGGAAGCTGAGCTGG 1860 AGCACCTAAGGCAGGCCCTGGACAGTGGCCTAGATACAAAAGAAGCCAAAGAAAAATTCC 1920 TCCATGAAGTTGTTAAAATGAGAGTGAAGCAGGAAGAGAAGCTAAATGCTGCCTTGCAAG 1980 CCAAACGCAGCCTACATCAGGAGCTGGAGTTCCTCAGAGTGGCAAAGAAGGAGAAACTGA 2040 GAGAAGCAACGGAGGCAAAACGCAACTTAAGGAAAGAGATTGAGCGTCTGAGAGCTGAGA 2100 ATGAGAAGAAAATGAAGGAAGCAAACGAGTCTCGGATACGGCTAAAGAGGGAACTGGAAC 2160 AAGCCAGGCAGATCCGGGTTTGCGACAAGGGTTGTGAAGCTGGCAGGCTTCGGGCCAAGT 2220 ACTCTGCCCAGATTGAGGACCTACAGGTTAAGCTTCAGCATGCAGAGGCTGACAGGGAGC 2280 AGCTCCGAGCTGACCTGATGCATGAGAGGGAGGCTCGAGAACACTTGGAAAAAGTAGTCA 2340 AGGAACTTCAGGAACAGCTGTGGCCTAAATCAAGCAGTCAATCCAGCAGTGAAAACACAA 2400 CGAGCAACATGGAGAATTAAACCACGTCGTCTAATACAACAGAATGACATATATGCACAG 2460 TAAGGGAGGATGGGTGGGGTACGTGTGTAAGTGCATGTGTGAGTAGTTGTGTCTTAACAC 2520 ACAGATCTAGGAATATGGATTCTTATTAGTTGGAAGGCAAATGTTACTCTTTATAACAGA 2580 AGCACTGAATTACGCCTCTTTTTTTTTCCAATCCATATAGCACAACATCTTACTGTGCCT 2640 ATAAAACACAAATGTGTTTATAAACAAAATACTTTTAAGTCCACAGCAAATTTTCTACTG 2700 GCAAACTCCAAGCAAGCAGCATCCTCCAACTAGAATCAGAGTAAAAGGCAAGCATGGCAG 2760 TGTTTTCATGTTGCCCTTCTGCCTGTCGGAACATTTTGGAATTTAAAAACAAACTTTTCT 2820 TATAAGCTATTTAAAGTAATTCATTACACAGACTTGGTATTAAAAAAAATTAACAAGATT 2880 TTTTATAACGAACCTTTAAAAGCAAAACAAAAACCTTCGATGCACAATTTTTACGACTTG 2940 TTAAAGGCTTTGGGATTCTTACTGCAGAAGCCCTTTGGTGATGATGCCATTTCATTAGCA 3000 GTTTTTTTTAATCCTGTCCTGTGGTTGTATGAGAATTTCAGAGTGCTTTTCAAAGTTGAT 3060 TTTTTTCCTTAGAAACAATCACCTTCATTTCCTGTCCTGAACACAAGAAGAAAGGAAGAT 3120 GCAGGACTGTAAGGGCGTGGGGGAGGGCAGGAAGAGAAGATGGACGCTTTGGAATTATAA 3180 ACCCAGCCTTACAGACTTCAGTGTTTCAAATCACGCCATGTTTTCTAAAGACGTCTTCAT 3240 TAATCGATGTGTTCAAAAGACTCACTTCATCCAAGAGCACTTCAGCTTTAGGAAAAGAAA 3300 GAAGGAAGTAAAGGAAGGAAATGGATGACCTGTTAAGTTGGTTGAGAAATAAAGCAGAAG 3360 ATGTGTTTTGAAGTCATTCTGAAATCTTCGCGTCAGCTTTCAGTTCTCTGGAAAACTCAT 3420 CTTTGTTGCACCATCTTACCATAGAATTCAGTATTTACCTACTTCTATTCTGAACTGTTT 3480 GTCAGGATTTCTGTGCCCAAGGAGAGTGCAACACCGCATTATTGGATACTACAGAAAAGA 3540 AAAACCACGTTTTTGCTGCTGTGAATAAGCCTACATCTTTTTTAAAAGAAAAACTTCTGT 3600 TTTTAAGAATAGAAATTACTTTAATTTTGGGATCCGAGCCGCAGCCCTGGAATAGAAATG 3660 CAGCCTACCATCACTCTGTCTTACTACCATTGTTAGCGTCGTCGTTCATTTTTTTTTAAA 3720 CTGCACTTTGTCAGAACCTCACTCTGCATTTTATTCCATATTTTGGAAGTTTACAAGTTC 3780 AGCATTCTCGATTCTGCTCTGCAGATGTTAAAATCATCACCACCATTTTCCACCACGCGA 3840 CACCTCGGCCGTCATTTCCATGTATGCAAAAGAAGAACTCAGTGGGTACAGAATGCTACC 3900 AAATACAAAGGCAGCAGAGCAGCGTGCTGCTGGTTGGGTTTCACAGCTGCGCTGCACGGC 3960 TGTGGCTGTCGAGGCTGGGAAGTGCTCAAATACAGTTGGTGCTTTACTGAATGAGAGAGG 4020 AGTTATTTTCACCCACACACACTCACCTCTGATACACTCAAGCTCAGTGAAAAGTTGATC 4080 TGGGGCTGCAGTTGTGCCTTCCAGCTCATTTTTCCTCTCAGCATCTTCTATAGGCAATGC 4140 TGACACTTTTTTTTTAAACCTTAAAGAATAAAAAG4175 (2) INFORMATION FOR SEQ ID NO:50: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1364 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:50: AAAATCAGGAACTTGTGCTGGCCCTGCAATGTCAAGGGAGGGGGCTCACCCAGGGCTCCT 60 GTAGCTCAGGGGGCAGGCCTGAGCCCTGCACCCGCCCCACGACCGTCCAGCCCCTGACGG 120 GCACCCCATCCTGAGGGGCTCTGCATTGGCCCCCACCGAGGCAGGGGATCTGACCGACTC 180 GGAGCCCGGCTGGATGTTACAGGCGTGCAAAATGGAAGGGTTTCCCCTCGTCCCCCCTCC 240 ATCAGAAGACCTGGTGCCCTATGACACGGATCTATACCAACGCCAAACGCACGAGTATTA 300 CCCCTATCTCAGCAGTGATGGGGAGAGCCATAGCGACCATTACTGGGACTTCCACCCCCA 360 CCACGTGCACAGCGAGTTCGAGAGCTTCGCCGAGAACAACTTCACGGAGCTCCAGAGCGT 420 GCAGCCCCCGCAGCTGCAGCAGCTCTACCGCCACATGGAGCTGGAGCAGATGCACGTCCT 480 CGATACCCCCATGGTGCCACCCCATCCCAGTCTTGGCCACCAGGTCTCCTACCTGCCCCG 540 GATGTGCCTCCAGTACCCATCCCTGTCCCCAGCCCAGCCCAGCTCAGATGAGGAGGAGGG 600 CGAGCGGCAGAGCCCCCCACTGGAGGTGTCTGACGGCGAGGCGGATGGCCTGGAGCCCGG 660 GCCTGGGCTCCTGCCTGGGGAGACAGGCAGCAAGAAGAAGATCCGCCTGTACCAGTTCCT 720 GTTGGACCTGCTCCGCAGCGGCGACATGAAGGACAGCATCTGGTGGGTGGACAAGGACAA 780 GGGCACCTTCCAGTTCTCGTCCAAGCACAAGGAGGCGCTGGCGCACCGCTGGGGCATCCA 840 GAAGGGCAACCGCAAGAAGATGACCTACCAGAAGATGGCGCGCGCGCTGCGCAACTACGG 900 CAAGACGGGCGAGGTCAAGAAGGTGAAGAAGAAGCTCACCTACCAGTTCAGCGGCGAAGT 960 GCTGGGCCGCGGGGGCCTGGCCGAGCGGCGCCACCCGCCCCACTGAGCCCGCAGCCCCCG 1020 CCGGCCCCGCCAGGCCTCCCCGCTGGCCATAGCATTAAGCCCTCGCCCGGCCCGGACACA 1080 GGGAGGACGCTCCCGGGGCCCAGAGGCAGGACTGTGGCGGGCCGGGCTCCGTCACCCGCC 1140 CCTCCCCCCACTCCAGGCCCCCTCCACATCCCGCTTCGCCTCCCTCCAGGACTCCACCCC 1200 GGCTCCCGACGCCAGCTGGGCGTCAGACCCACCGGCAACCTTGCAGAGGACGACCCGGGG 1260 TACTGCCTTGGGAGTCTCAAGTCCGTATGTAAATCAGATCTCCCCTCTCACCCCTCCCAC 1320 CCATTAACCTCCTCCCAAAAAACAAGTAAAGTTATTCTCAATCC1364 (2) INFORMATION FOR SEQ ID NO:51: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1325 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51: GCAGTAGCAGCGAGCAGCAGAGTCCGCACGCTCCGGCGAGGGGCAGAAGAGCGCGAGGGA 60 GCGCGGGGCAGCAGAAGCGAGAGCCGAGCGCGGACCCAGCCAGGACCCACAGCCCTCCCC 120 AGCTGCCCAGGAAGAGCCCCAGCCATGGAACACCAGCTCCTGTGCTGCGAAGTGGAAACC 180 ATCCGCCGCGCGTACCCCGATGCCAACCTCCTCAACGACCGGGTGCTGCGGGCCATGCTG 240 AAGGCGGAGGAGACCTGCGCGCCCTCGGTGTCCTACTTCAAATGTGTGCAGAAGGAGGTC 300 CTGCCGTCCATGCGGAAGATCGTCGCCACCTGGATGCTGGAGGTCTGCGAGGAACAGAAG 360 TGCGAGGAGGAGGTCTTCCCGCTGGCCATGAACTACCTGGACCGCTTCCTGTCGCTGGAG 420 CCCGTGAAAAAGAGCCGCCTGCAGCTGCTGGGGGCCACTTGCATGTTCGTGGCCTCTAAG 480 ATGAAGGAGACCATCCCCCTGACGGCCGAGAAGCTGTGCATCTACACCGACGGCTCCATC 540 CGGCCCGAGGAGCTGCTGCAAATGGAGCTGCTCCTGGTGAACAAGCTCAAGTGGAACCTG 600 GCCGCAATGACCCCGCACGATTTCATTGAACACTTCCTCTCCAAAATGCCAGAGGCGGAG 660 GAGAACAAACAGATCATCCGCAAACACGCGCAGACCTTCGTTGCCTCTTGTGCCACAGAT 720 GTGAAGTTCATTTCCAATCCGCCCTCCATGGTGGCAGCGGGGAGCGTGGTGGCCGCAGTG 780 CAAGGCCTGAACCTGAGGAGCCCCAACAACTTCCTGTCCTACTACCGCCTCACACGCTTC 840 CTCTCCAGAGTGATCAAGTGTGACCCAGACTGCCTCCGGGCCTGCCAGGAGCAGATCGAA 900 GCCCTGCTGGAGTCAAGCCTGCGCCAGGCCCAGCAGAACATGGACCCCAAGGCCGCCGAG 960 GAGGAGGAAGAGGAGGAGGAGGAGGTGGACCTGGCTTGCACACCCACCGACGTGCGGGAC 1020 GTGGACATCTGAGGGGCCCAGGCAGGCGGGCGCCACCGCCACCCGCAGCGAGGGCGGAGC 1080 CGGCCCCAGGTGCTCCACATGACAGTCCCTCCTCTCCGGAGCATTTTGATACCAGAAGGG 1140 AAAGCTTCATTCTCCTTGTTGTTGGTTGTTTTTTCCTTTGCTCTTTCCCCCTTCCATCTC 1200 TGACTTAAGCAAAAGAAAAAGATTACCCAAAAACTGTCTTTAAAAGAGAGAGAGAGAAAA 1260 AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA 1320 AAAAA1325 (2) INFORMATION FOR SEQ ID NO:52: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 3036 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52: CTCCCCTTCAGCTTCTCTTCACGCACTCCAAGATCTAAACCGAGAATCGAAACTAAGCTG 60 GGGTCCATGGAGCCTGCACCCGCCCGATCTCCGAGGCCCCAGCAGGACCCCGCCCGGCCC 120 CAGGAGCCCACCATGCCTCCCCCCGAGACCCCCTCTGAAGGCCGCCAGCCCAGCCCCAGC 180 CCCAGCCCTACAGAGCGAGCCCCCGCTTCGGAGGAGGAGTTCCAGTTTCTGCGCTGCCAG 240 CAATGCCAGGCGGAAGCCAAGTGCCCGAAGCTGCTGCCTTGTCTGCACACGCTGTGCTCA 300 GGATGCCTGGAGGCGTCGGGCATGCAGTGCCCCATCTGCCAGGCGCCCTGGCCCCTAGGT 360 GCAGACACACCCGCCCTGGATAACGTCTTTTTCGAGAGTCTGCAGCGGCGCCTGTCGGTG 420 TACCGGCAGATTGTGGATGCGCAGGCTGTGTGCACCCGCTGCAAAGAGTCGGCCGACTTC 480 TGGTGCTTTGAGTGCGAGCAGCTCCTCTGCGCCAAGTGCTTCGAGGCACACCAGTGGTTC 540 CTCAAGCACGAGGCCCGGCCCCTAGCAGAGCTGCGCAACCAGTCGGTGCGTGAGTTCCTG 600 GACGGCACCCGCAAGACCAACAACATCTTCTGCTCCAACCCCAACCACCGCACCCCTACG 660 CTGACCAGCATCTACTGCCGAGGATGTTCCAAGCCGCTGTGCTGCTCGTGCGCGCTCCTT 720 GACAGCAGCCACAGTGAGCTCAAGTGCGACATCAGCGCAGAGATCCAGCAGCGACAGGAG 780 GAGCTGGACGCCATGACGCAGGCGCTGCAGGAGCAGGATAGTGCCTTTGGCGCGGTTCAC 840 GCGCAGATGCACGCGGCCGTCGGCCAGCTGGGCCGCGCGCGTGCCGAGACCGAGGAGCTG 900 ATCCGCGAGCGCGTGCGCCAGGTGGTAGCTCACGTGCGGGCTCAGGAGCGCGAGCTGCTG 960 GAGGCTGTGGACGCGCGGTACCAGCGCGACTACGAGGAGATGGCCAGTCGGCTGGGCCGC 1020 CTGGATGCTGTGCTGCAGCGCATCCGCACGGGCAGCGCGCTGGTGCAGAGGATGAAGTGC 1080 TACGCCTCGGACCAGGAGGTGCTGGACATGCACGGTTTCCTGCGCCAGGCGCTCTGCCGC 1140 CTGCGCCAGGAGGAGCCCCAGAGCCTGCAAGCTGCCGTGCGCACCGATGGCTTCGACGAG 1200 TTCAAGGTGCGCCTGCAGGACCTCAGCTCTTGCATCACCCAGGGGAAAGCCATTGAGACC 1260 CAGAGCAGCAGTTCTGAAGAGATAGTGCCCAGCCCTCCCTCGCCACCCCCTCTACCCCGC 1320 ATCTACAAGCCTTGCTTTGTCTGTCAGGACAAGTCCTCAGGCTACCACTATGGGGTCAGC 1380 GCCTGTGAGGGCTGCAAGGGCTTCTTCCGCCGCAGCATCCAGAAGAACATGGTGTACACG 1440 TGTCACCGGGACAAGAACTGCATCATCAACAAGGTGACCCGGAACCGCTGCCAGTACTGC 1500 CGACTGCAGAAGTGCTTTGAAGTGGGCATGTCCAAGGAGTCTGTGAGAAACGACCGAAAC 1560 AAGAAGAAGAAGGAGGTGCCCAAGCCCGAGTGCTCTGAGAGCTACACGCTGACGCCGGAG 1620 GTGGGGGAGCTCATTGAGAAGGTGCGCAAAGCGCACCAGGAAACCTTCCCTGCCCTCTGC 1680 CAGCTGGGCAAATACACTACGAACAACAGCTCAGAACAACGTGTCTCTCTGGACATTGAC 1740 CTCTGGGACAAGTTCAGTGAACTCTCCACCAAGTGCATCATTAAGACTGTGGAGTTCGCC 1800 AAGCAGCTGCCCGGCTTCACCACCCTCACCATCGCCGACCAGATCACCCTCCTCAAGGCT 1860 GCCTGCCTGGACATCCTGATCCTGCGGATCTGCACGCGGTACACGCCCGAGCAGGACACC 1920 ATGACCTTCTCGGACGGGCTGACCCTGAACCGGACCCAGATGCACAACGCTGGCTTCGGC 1980 CCCCTCACCGACCTGGTCTTTGCCTTCGCCAACCAGCTGCTGCCCCTGGAGATGGATGAT 2040 GCGGAGACGGGGCTGCTCAGCGCCATCTGCCTCATCTGCGGAGACCGCCAGGACCTGGAG 2100 CAGCCGGACCGGGTGGACATGCTGCAGGAGCCGCTGCTGGAGGCGCTAAAGGTCTACGTG 2160 CGGAAGCGGAGGCCCAGCCGCCCCCACATGTTCCCCAAGATGCTAATGAAGATTACTGAC 2220 CTGCGAAGCATCAGCGCCAAGGGGGCTGAGCGGGTGATCACGCTGAAGATGGAGATCCCG 2280 GGCTCCATGCCGCCTCTCATCCAGGAAATGTTGGAGAACTCAGAGGGCCTGGACACTCTG 2340 AGCGGACAGCCGGGGGGTGGGGGGCGGGACGGGGGTGGCCTGGCCCCCCCGCCAGGCAGC 2400 TGTAGCCCCAGCCTCAGCCCCAGCTCCAACAGAAGCAGCCCGGCCACCCACTCCCCGTGA 2460 CCGCCCACGCCACATGGACACAGCCCTCGCCCTCCGCCCCGGCTTTTCTCTGCCTTTCTA 2520 CCGACCATGTGACCCCGCACCAGCCCTGCCCCCACCTGCCCTCCCGGGCAGTACTGGGGA 2580 CCTTCCCTGGGGGACGGGGAGGGAGGAGGCAGCGACTCCTTGGACAGAGGCCTGGGCCCT 2640 CAGTGGACTGCCTGCTCCCACAGCCTGGGCTGACGTCAGAGGCCGAGGCCAGGAACTGAG 2700 TGAGGCCCCTGGTCCTGGGTCTCAGGATGGGTCCTGGGGGCCTCGTGTTCATCAAGACAC 2760 CCCTCTGCCCAGCTCACCACATCTTCATCACCAGCAAACGCCAGGACTTGGCTCCCCCAT 2820 CCTCAGAACTCACAAGCCATTGCTCCCCAGCTGGGGAACCTCAACCTCCCCCCTGCCTCG 2880 GTTGGTGACAGAGGGGGTGGGACAGGGGCGGGGGGTTCCCCCTGTACATACCCTGCCATA 2940 CCAACCCCAGGTATTAATTCTCGCTGGTTTTGTTTTTATTTTAATTTTTTTGTTTTGATT 3000 TTTTTAATAAGAATTTTCATTTTAAGCAAAAAAAAA3036 (2) INFORMATION FOR SEQ ID NO:53: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4287 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53: CATAGAGCCAGCGGGCGCGGGCGGGACGGGCGCCCCGCGGCCGGACCCAGCCAGGGCACC 60 ACGCTGCCCGGCCCTGCGCCGCCAGGCACTTCTTTCCGGGGCTCCTAGGGACGCCAGAAG 120 GAAGTCAACCTCTGCTGCTTCTCCTTGGCCTGCGTTGGACCTTCCTTTTTTTGTTGTTTT 180 TTTTTGTTTTTCCCCTTTCTTCCTTTTGAATTAACTGGCTTCTTGGCTGGATGTTTTCAA 240 CTTCTTTCCTGGCTGCGAACTTTTCCCCAATTGTTTTCCTTTTACAACAGGGGGAGAAAG 300 TGCTCTGTGGTCCGAGGCGAGCCGTGAAGTTGCGTGTGCGTGGCAGTGTGCGTGGCAGGA 360 TGTGCGTGCGTGTGTAACCCGAGCCGCCCGATCTGTTTCGATCTGCGCCGCGGAGCCCTC 420 CCTCAAGGCCCGCTCCACCTGCTGCGGTTACGCGGCGCTCGTGGGTGTTCGTGCCTCGGA 480 GCAGCTAACCGGCGGGTGCTGGGCGACGGTGGAGGAGTATCGTCTCGCTGCTGCCCGAGT 540 CAGGGCTGAGTCACCCAGCTGATGTAGACAGTGGCTGCCTTCCGAAGAGTGCGTGTTTGC 600 ATGTGTGTGACTCTGCGGCTGCTCAACTCCCAACAAACCAGAGGACCAGCCACAAACTTA 660 ACCAACATCCCCAAACCCGAGTTCACAGATGTGGGAGAGCTGTAGAACCCTGAGTGTCAT 720 CGACTGGGCCTTCTTATGATTGTTGTTTTAAGATTAGCTGAAGATCTCTGAAACGCTGAA 780 TTTTCTGCACTGAGCGTTTTGACAGAATTCATTGAGAGAACAGAGAACATGACAAGTACT 840 TCTAGCTCAGCACTGCTCCAACTACTGAAGCTGATTTTCAAGGCTACTTAAAAAAATCTG 900 CAGCGTACATTAATGGATTTCTGTTGTGTTTAAATTCTCCACAGATTGTATTGTAAATAT 960 TTTATGAAGTAGAGCATATGTATATATTTATATATACGTGCACATACATTAGTAGCACTA 1020 CCTTTGGAAGTCTCAGCTCTTGCTTTTCGGGACTGAAGCCAGTTTTGCATGATAAAAGTG 1080 GCCTTGTTACGGGAGATAATTGTGTTCTGTTGGGACTTTAGACAAAACTCACCTGCAAAA 1140 AACTGACAGGCATTAACTACTGGAACTTCCAAATAATGTGTTTGCTGATCGTTTTACTCT 1200 TCGCATAAATATTTTAGGAAGTGTATGAGAATTTTGCCTTCAGGAACTTTTCTAACAGCC 1260 AAAGACAGAACTTAACCTCTGCAAGCAAGATTCGTGGAAGATAGTCTCCACTTTTTAATG 1320 CACTAAGCAATCGGTTGCTAGGAGCCCATCCTGGGTCAGAGGCCGATCCGCAGAACCAGA 1380 ACGTTTTCCCCTCCTGGACTGTTAGTAACTTAGTCTCCCTCCTCCCCTAACCACCCCCGC 1440 CCCCCCCCACCCCCCGCAGTAATAAAGGCCCCTGAACGTGTATGTTGGTCTCCCGGGAGC 1500 TGCTTGCTGAAGATCCGCGCCCCTGTCGCCGTCTGGTAGGAGCTGTTTGCAGGGTCCTAA 1560 CTCAATCGGCTTGTTGTGATGCGTATCCCCGTAGATGCCAGCACGAGCCGCCGCTTCACG 1620 CCGCCTTCCACCGCGCTGAGCCCAGGCAAGATGAGCGAGGCGTTGCCGCTGGGCGCCCCG 1680 GACGCCGGCGCTGCCCTGGCCGGCAAGCTGAGGAGCGGCGACCGCAGCATGGTGGAGGTG 1740 CTGGCCGACCACCCGGGCGAGCTGGTGCGCACCGACAGCCCCAACTTCCTCTGCTCCGTG 1800 CTGCCTACGCACTGGCGCTGCAACAAGACCCTGCCCATCGCTTTCAAGGTGGTGGCCCTA 1860 GGGGATGTTCCAGATGGCACTCTGGTCACTGTGATGGCTGGCAATGATGAAAACTACTCG 1920 GCTGAGCTGAGAAATGCTACCGCAGCCATGAAGAACCAGGTTGCAAGATTTAATGACCTC 1980 AGGTTTGTCGGTCGAAGTGGAAGAGGGAAAAGCTTCACTCTGACCATCACTGTCTTCACA 2040 AACCCACCGCAAGTCGCCACCTACCACAGAGCCATCAAAATCACAGTGGATGGGCCCCGA 2100 GAACCTCGAAATCGTACTGAGAAGCACTCCACAATGCCAGACTCACCTGTGGATGTGAAG 2160 ACGCAATCTAGGCTGACTCCTCCAACAATGCCACCTCCCCCAACTACTCAAGGAGCTCCA 2220 AGAACCAGTTCATTTACACCGACAACGTTAACTAATGGCACGAGCCATTCTCCTACAGCC 2280 TTGAATGGCGCCCCCTCACCACCCAATGGCTTCAGCAATGGGCCTTCCTCTTCTTCCTCC 2340 TCCTCTCTGGCTAATCAACAGCTGCCCCCAGCCTGTGGTGCCAGGCAACTCAGCAAGCTG 2400 AAAAGGTTCCTTACTACCCTGCAGCAGTTTGGCAATGACATTTCACCCGAGATAGGAGAA 2460 AGAGTTCGCACCCTCGTTCTGGGACTAGTGAACTCCACTTTGACAATTGAAGAATTTCAT 2520 TCCAAACTGCAAGAAGCTACTAACTTCCCACTGAGACCTTTTGTCATCCCATTTTTGAAG 2580 GCCAACTTGCCCCTGCTGCAGCGTGAGCTCCTCCACTGCGCAAGACTGGCCAAACAGAAC 2640 CCTGCCCAGTACCTCGCCCAGCATGAACAGCTGCTTCTGGATGCCAGCACCACCTCACCT 2700 GTTGACTCCTCAGAGCTGCTTCTCGATGTGAACGAAAACGGGAAGAGGCGAACTCCAGAC 2760 AGAACCAAAGAAAATGGCTTTGACAGAGAGCCTTTGCACTCAGAACATCCAAGCAAGCGA 2820 CCATGCACTATTAGCCCAGGCCAGCGGTACAGTCCAAATAACGGCTTATCCTACCAGCCC 2880 AATGGCCTGCCTCACCCTACCCCACCTCCACCTCAGCATTACCGTTTGGATGATATGGCC 2940 ATTGCCCACCACTACAGGGACTCCTATCGACACCCCAGCCACAGGGACCTCAGGGACAGA 3000 AACAGACCTATGGGGTTGCATGGCACACGTCAAGAAGAAATGATTGATCACAGACTAACA 3060 GACAGAGAATGGGCAGAAGAGTGGAAACATCTTGACCATCTGTTAAACTGCATAATGGAC 3120 ATGGTAGAAAAAACAAGGCGATCTCTCACCGTACTAAGGCGGTGTCAAGAAGCAGACCGG 3180 GAAGAATTGAATTACTGGATCCGGCGGTACAGTGACGCCGAGGACTTAAAAAAAGGTGGC 3240 GGCAGTAGCAGCAGCCACTCTAGGCAGCAGAGTCCCGTCAACCCAGACCCAGTTGCACTA 3300 GACGCGCATCGGGAATTCCTTCACAGGCCTGCGTCTGGATACGTGCCAGAGGAGATCTGG 3360 AAGAAAGCTGAGGAGGCCGTCAATGAGGTGAAGCGCCAGGCGATGACGGAGCTGCAGAAG 3420 GCCGTGTCTGAGGCGGAGCGGAAAGCCCACGACATGATCACAACAGAGAGGGCCAAGATG 3480 GAGCGCACGGTCGCCGAGGCCAAACGGCAGGCGGCGGAGGACGCACTGGCAGTTATCAAT 3540 CAGCAGGAGGATTCAAGCGAGAGTTGCTGGAATTGTGGCCGTAAAGCGAGTGAAACCTGC 3600 AGTGGCTGTAACACAGCCCGATACTGTGGCTCATTTTGCCAGCACAAAGACTGGGAGAAG 3660 CACCATCACATCTGTGGACAGACCCTGCAGGCCCAGCAGCAGGGAGACACACCTGCAGTC 3720 AGCTCCTCTGTCACGCCCAACAGCGGGGCTGGGAGCCCGATGGACACACCACCAGCAGCC 3780 ACTCCGAGGTCAACCACCCCGGGAACCCCTTCCACCATAGAGACAACCCCTCGCTAGACG 3840 TGAACTCAGAACTGTCGGAGGAAAGACAACACAACCAACGCGAAACCAATTCCTCATCCT 3900 CAGATGCTCAAAGTTGTTTTTTTTGTTTGTTTGTTTATTAGATGAATTATCCTATTTCAG 3960 TACTTCAGCAAGAGAGAACCTAACTGTATCTTGAGGTGGTAGTAAAACACAGAGGGCCAG 4020 TAACGGGTCGTAATGACTTATTGTGGATAACAAAGATATCTTTTCTTTAGAGAACTGAAA 4080 AGAGAGCAGAGAATATAACATGAAATGATAGATTTGACCTCCTCCCTGTTATTTTCAAGT 4140 AGCTGGGATTTTAAACTAGATGACCTCATTAACCGATGCTTTACCAAACAGCAAACCAAG 4200 AGATTGCTAATTGCTGTTGAAAGCAAAAATGCTAATATTAAAAGTCACAATGTTCTTTAT 4260 ATACAATAATGGAAAAAAAAAAAAAAA4287 (2) INFORMATION FOR SEQ ID NO:54: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2952 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54: ACGCGCCGCGTGCCCGGCCGCGCCCAGCAGGGTTTCCAGGCCTGAGGTGCCCGCCCTGGC 60 CCCAGGAGAATGAACCAGCCGCAGAGGATGGCGCCTGTGGGCACAGACAAGGAGCTCAGT 120 GACCTCCTGGACTTCAGCATGATGTTCCCGCTGCCTGTCACCAACGGGAAGGGCCGGCCC 180 GCCTCCCTGGCCGGGGCGCAGTTCGGAGGTTCAGGTCTTGAGGACCGGCCCAGCTCAGGC 240 TCCTGGGGCAGCGGCGACCAGAGCAGCTCCTCCTTTGACCCCAGCCGGACCTTCAGCGAG 300 GGCACCCACTTCACTGAGTCGCACAGCAGCCTCTCTTCATCCACATTCCTGGGACCGGGA 360 CTCGGAGGCAAGAGCGGTGAGCGGGGCGCCTATGCCTCCTTCGGGAGAGACGCAGGCGTG 420 GGCGGCCTGACTCAGGCTGGCTTCCTGTCAGGCGAGCTGGCCCTCAACAGCCCCGGGCCC 480 CTGTCCCCTTCGGGCATGAAGGGGACCTCCCAGTACTACCCCTCCTACTCCGGCAGCTCC 540 CGGCGGAGAGCGGCAGACGGCAGCCTAGACACGCAGCCCAAGAAGGTCCGGAAGGTCCCG 600 CCGGGTCTTCCATCCTCGGTGTACCCACCCAGCTCAGGTGAGGACTACGGCAGGGATGCC 660 ACCGCCTACCCGTCCGCCAAGACCCCCAGCAGCACCTATCCCGCCCCCTTCTACGTGGCA 720 GATGGCAGCCTGCACCCCTCAGCCGAGCTCTGGAGTCCCCCGGGCCAGGCGGGCTTCGGG 780 CCCATGCTGGGTGGGGGCTCATCCCCGCTGCCCCTCCCGCCCGGTAGCGGCCCGGTGGGC 840 AGCAGTGGAAGCAGCAGCACGTTTGGTGGCCTGCACCAGCACGAGCGTATGGGCTACCAG 900 CTGCATGGAGCAGAGGTGAACGGTGGGCTCCCATCTGCATCCTCCTTCTCCTCAGCCCCC 960 GGAGCCACGTACGGCGGCGTCTCCAGCCACACGCCGCCTGTCAGCGGGGCCGACAGCCTC 1020 CTGGGCTCCCGAGGGACCACAGCTGGCAGCTCCGGGGATGCCCTCGGCAAAGCACTGGCC 1080 TCGATCTACTCCCCGGATCACTCAAGCAATAACTTCTCGTCCAGCCCTTCTACCCCCGTG 1140 GGCTCCCCCCAGGGCCTGGCAGGAACGTCACAGTGGCCTCGAGCAGGAGCCCCCGGTGCC 1200 TTATCGCCCAGCTACGACGGGGGTCTCCACGGCCTGCAGAGTAAGATAGAAGACCACCTG 1260 GACGAGGCCATCCACGTGCTCCGCAGCCACGCCGTGGGCACAGCCGGCGACATGCACACG 1320 CTGCTGCCTGGCCACGGGGCGCTGGCCTCAGGTTTCACCGGCCCCATGTCACTGGGCGGG 1380 CGGCACGCAGGCCTGGTTGGAGGCAGCCACCCCGAGGACGGCCTCGCAGGCAGCACCAGC 1440 CTCATGCACAACCACGCGGCCCTCCCCAGCCAGCCAGGCACCCTCCCTGACCTGTCTCGG 1500 CCTCCCGACTCCTACAGTGGTTTTGAGTATCCGAGGAGCCCAGGAGGAGGAACCCACAGA 1560 CCCCCAGCTGATGCGGCTGGACAACATGCTGTTAGCGGAAGGCGTGGCGGGGCCTGAGAA 1620 GGGCGGAGGGTCGGCGGCAGCGGCGGCAGCGGCGGCGGCTTCTGGAGGGGCAGGTTCAGA 1680 CAACTCAGTGGAGCATTCAGATTACAGAGCCAAACTCTCACAGATCAGACAAATCTACCA 1740 TACGGAGCTGGAGAAATACGAGCAGGCCTGCAACGAGTTCACCACCCACGTGATGAATCT 1800 CCTGCGAGACGAAAGCCGGACCAGGCCCATCTCCCCAAAGGAGATTGAGCGGATGGTCAG 1860 CATCATCCACCGCAAGTTCAGCTCCATCCAGATGCAGCTCAAGCAGAGCACGTGCGAGGC 1920 GGTGATGATCCTGCGTTCCCGATTTCTGGATGCGCGGCGGAAGAGACGGAATTTCAACAA 1980 GCAAGCGACAGAAATCCTGAATGAATATTTCTATTCCCATCTCAGCAACCCTTACCCCAG 2040 TGAGGAAGCCAAAGAGGAGTTAGCCAAGAAGTGTGGCATCACAGTCTCCCAGGTATCAAA 2100 CTGGTTTGGAAATAAGCGAATCCGGTACAAGAAGAACATAGGTAAATTTCAAGAGGAAGC 2160 CAATATTTATGCTGCCAAAACAGCTGTCACTGCTACCAATGTGTCAGCCCATGGAAGCCA 2220 AGCTAACTCGCCCTCAACTCCCAACTCGGCTGGTTCTTCCAGTTCTTTTAACATGTCAAA 2280 CTCTGGAGATTTGTTCATGAGCGTGCAGTCACTCAATGGGGATTCTTACCAAGGGGCCCA 2340 GGTTGGAGCCAACGTGCAATCACAGGTGGATACCCTTCGCCATGTTATCAGCCAGACAGG 2400 AGGATACAGTGATGGACTCGCAGCCAGTCAGATGTACAGTCCGCAGGGCATCAGTGCTAA 2460 TGGAGGTTGGCAGGATGCTACTACCCCTTCATCAGTGACCTCCCCTACAGAAGGCCCTGG 2520 CAGTGTTCACTCTGATACCTCCAACTGATCTCCCAGCAATCGCATCCCGGCTGACCCTCT 2580 GCCCCAGTTGGGGCAGGGGCAGGAGGGAGGGTTTCTCTCCCAAAGCTGAAGCGGTCAGAC 2640 TGGAGGTCGAAGCAATCAGCAAACACAATAAGAGTCTCCTTCTCTTCTCTTCTTTGGGAT 2700 GCTATTTCAGCCAATCTGGACACTTCTTTATACTCTCTTCCCTTTTTTTTCTGGGTAGAA 2760 GCCACCCTTCCCTGCCTCCAGCTGTCAGCCTGGTTTTCGTCATCTTCCCTGCCCCTGTGC 2820 CTCTGTCCTAGACTTCCCGGGGTCCCCGCCCTCTCTCATATCACTGAAGGATATTTTCAA 2880 CAATTAGAGGAATTTAAAGAGGAAAAAAATTACAAAGAAAATAATAAAAGTGTTTGTACG 2940 TTTTCAAAAAAA2952 (2) INFORMATION FOR SEQ ID NO:55: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14255 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:55: GCGGCGGCGGCGGCGGGAAGCAGCGGGGCTGGGGTTCCAGGGGGAGCGGCCGCCGCCTCA 60 GCAGCCTCCTCGTCGTCCGCCTCGTCTTCGTCTTCGTCATCGTCCTCAGCCTCTTCAGGG 120 CCGGCCCTGCTCCGGGTGGGCCCGGGCTTCGACGCGGCGCTGCAGGTCTCGGCCGCCATC 180 GGCACCAACCTGCGCCGGTTCCGGGCCGTGTTTGGGGAGAGCGGCGGGGGAGGCGGCAGC 240 GGAGAGGATGAGCAATTCTTAGGTTTTGGCTCAGATGAAGAAGTCAGAGTGCGAAGTCCC 300 ACAAGGTCTCCTTCAGTTAAAACTAGTCCTCGAAAACCTCGTGGGAGACCTAGAAGTGGC 360 TCTGACCGAAATTCAGCTATCCTCTCAGATCCATCTGTGTTTTCCCCTCTAAATAAATCA 420 GAGACCAAATCTGGAGATAAGATCAAGAAGAAAGATTCTAAAAGTATAGAAAAGAAGAGA 480 GGAAGACCTCCCACCTTCCCTGGAGTAAAAATCAAAATAACACATGGAAAGGACATTTCA 540 GAGTTACCAAAGGGAAACAAAGAAGATAGCCTGAAAAAAATTAAAAGGACACCTTCTGCT 600 ACGTTTCAGCAAGCCACAAAGATTAAAAAATTAAGAGCAGGTAAACTCTCTCCTCTCAAG 660 TCTAAGTTTAAGACAGGGAAGCTTCAAATAGGAAGGAAGGGGGTACAAATTGTACGACGG 720 AGAGGAAGGCCTCCATCAACAGAAAGGATAAAGACCCCTTCGGGTCTCCTCATTAATTCT 780 GAACTGGAAAAGCCCCAGAAAGTCCGGAAAGACAAGGAAGGAACACCTCCACTTACAAAA 840 GAAGATAAGACAGTTGTCAGACAAAGCCCTCGAAGGATTAAGCCAGTTAGGATTATTCCT 900 TCTTCAAAAAGGACAGATGCAACCATTGCTAAGCAACTCTTACAGAGGGCAAAAAAGGGG 960 GCTCAAAAGAAAATTGAAAAAGAAGCAGCTCAGCTGCAGGGAAGAAAGGTGAAGACACAG 1020 GTCAAAAATATTCGACAGTTCATCATGCCTGTTGTCAGTGCTATCTCCTCGCGGATCATT 1080 AAGACCCCTCGGCGGTTTATAGAGGATGAGGATTATGACCCTCCAATTAAAATTGCCCGA 1140 TTAGAGTCTACACCGAATAGTAGATTCAGTGCCCCGTCCTGTGGATCTTCTGAAAAATCA 1200 AGTGCAGCTTCTCAGCACTCCTCTCAAATGTCTTCAGACTCCTCTCGATCTAGTAGCCCC 1260 AGTGTTGATACCTCCACAGACTCTCAGGCTTCTGAGGAGATTCAGGTACTTCCTGAGGAG 1320 CGGAGCGATACCCCTGAAGTTCATCCTCCACTGCCCATTTCCCAGTCCCCAGAAAATGAG 1380 AGTAATGATAGGAGAAGCAGAAGGTATTCAGTGTCGGAGAGAAGTTTTGGATCTAGAACG 1440 ACGAAAAAATTATCAACTCTACAAAGTGCCCCCCAGCAGGAGACCTCCTCGTCTCCACCT 1500 CCACCTCTGCTGACTCCACCGCCACCACTGCAGCCAGCCTCCAGTATCTCTGACCACACA 1560 CCTTGGCTTATGCCTCCAACAATCCCCTTAGCATCACCATTTTTGCCTGCTTCCACTGCT 1620 CCTATGCAAGGGAAGCGAAAATCTATTTTGCGAGAACCGACATTTAGGTGGACTTCTTTA 1680 AAGCATTCTAGGTCAGAGCCACAATACTTTTCCTCAGCAAAGTATGCCAAAGAAGGTCTT 1740 ATTCGCAAACCAATATTTGATAATTTCCGACCCCCTCCACTAACTCCCGAGGACGTTGGC 1800 TTTGCATCTGGTTTTTCTGCATCTGGTACCGCTGCTTCAGCCCGATTGTTTTCGCCACTC 1860 CATTCTGGAACAAGGTTTGATATGCACAAAAGGAGCCCTCTTCTGAGAGCTCCAAGATTT 1920 ACTCCAAGTGAGGCTCACTCTAGAATATTTGAGTCTGTAACCTTGCCTAGTAATCGAACT 1980 TCTGCTGGAACATCTTCTTCAGGAGTATCCAATAGAAAAAGGAAAAGAAAAGTGTTTAGT 2040 CCTATTCGATCTGAACCAAGATCTCCTTCTCACTCCATGAGGACAAGAAGTGGAAGGCTT 2100 AGTAGTTCTGAGCTCTCACCTCTCACCCCCCCGTCTTCTGTCTCTTCCTCGTTAAGCATT 2160 TCTGTTAGTCCTCTTGCCACTAGTGCCTTAAACCCAACTTTTACTTTTCCTTCTCATTCC 2220 CTGACTCAGTCTGGGGAATCTGCAGAGAAAAATCAGAGACCAAGGAAGCAGACTAGTGCT 2280 CCGGCAGAGCCATTTTCATCAAGTAGTCCTACTCCTCTCTTCCCTTGGTTTACCCCAGGC 2340 TCTCAGACTGAAAGAGGGAGAAATAAAGACAAGGCCCCCGAGGAGCTGTCCAAAGATCGA 2400 GATGCTGACAAGAGCGTGGAGAAGGACAAGAGTAGAGAGAGAGACCGGGAGAGAGAAAAG 2460 GAGAATAAGCGGGAGTCAAGGAAAGAGAAAAGGAAAAAGGGATCAGAAATTCAGAGTAGT 2520 TCTGCTTTGTATCCTGTGGGTAGGGTTTCCAAAGAGAAGGTTGTTGGTGAAGATGTTGCC 2580 ACTTCATCTTCTGCCAAAAAAGCAACAGGGCGGAAGAAGTCTTCATCACATGATTCTGGG 2640 ACTGATATTACTTCTGTGACTCTTGGGGATACAACAGCTGTCAAAACCAAAATACTTATA 2700 AAGAAAGGGAGAGGAAATCTGGAAAAAACCAACTTGGACCTCGGCCCAACTGCCCCATCC 2760 CTGGAGAAGGAGAAAACCCTCTGCCTTTCCACTCCTTCATCTAGCACTGTTAAACATTCC 2820 ACTTCCTCCATAGGCTCCATGTTGGCTCAGGCAGACAAGCTTCCAATGACTGACAAGAGG 2880 GTTGCCAGCCTCCTAAAAAAGGCCAAAGCTCAGCTCTGCAAGATTGAGAAGAGTAAGAGT 2940 CTTAAACAAACCGACCAGCCCAAAGCACAGGGTCAAGAAAGTGACTCATCAGAGACCTCT 3000 GTGCGAGGACCCCGGATTAAACATGTCTGCAGAAGAGCAGCTGTTGCCCTTGGCCGAAAA 3060 CGAGCTGTGTTTCCTGATGACATGCCCACCCTGAGTGCCTTACCATGGGAAGAACGAGAA 3120 AAGATTTTGTCTTCCATGGGGAATGATGACAAGTCATCAATTGCTGGCTCAGAAGATGCT 3180 GAACCTCTTGCTCCACCCATCAAACCAATTAAACCTGTCACTAGAAACAAGGCACCCCAG 3240 GAACCTCCAGTAAAGAAAGGACGTCGATCGAGGCGGTGTGGGCAGTGTCCCGGCTGCCAG 3300 GTGCCTGAGGACTGTGGTGTTTGTACTAATTGCTTAGATAAGCCCAAGTTTGGTGGTCGC 3360 AATATAAAGAAGCAGTGCTGCAAGATGAGAAAATGTCAGAATCTACAATGGATGCCTTCC 3420 AAAGCCTACCTGCAGAAGCAAGCTAAAGCTGTGAAAAAGAAAGAGAAAAAGTCTAAGACC 3480 AGTGAAAAGAAAGACAGCAAAGAGAGCAGTGTTGTGAAGAACGTGGTGGACTCTAGTCAG 3540 AAACCTACCCCATCAGCAAGAGAGGATCCTGCCCCAAAGAAAAGCAGTAGTGAGCCTCCT 3600 CCACGAAAGCCCGTCGAGGAAAAGAGTGAAGAAGGGAATGTCTCGGCCCCTGGGCCTGAA 3660 TCCAAACAGGCCACCACTCCAGCTTCCAGGAAGTCAAGCAAGCAGGTCTCCCAGCCAGCA 3720 CTGGTCATCCCGCCTCAGCCACCTACTACAGGACCGCCAAGAAAAGAAGTTCCCAAAACC 3780 ACTCCTAGTGAGCCCAAGAAAAAGCAGCCTCCACCACCAGAATCAGGTCCAGAGCAGAGC 3840 AAACAGAAAAAAGTGGCTCCCCGCCCAAGTATCCCTGTAAAACAAAAACCAAAAGAAAAG 3900 GAAAAACCACCTCCGGTCAATAAGCAGGAGAATGCAGGCACTTTGAACATCCTCAGCACT 3960 CTCTCCAATGGCAATAGTTCTAAGCAAAAAATTCCAGCAGATGGAGTCCACAGGATCAGA 4020 GTGGACTTTAAGGAGGATTGTGAAGCAGAAAATGTGTGGGAGATGGGAGGCTTAGGAATC 4080 TTGACTTCTGTTCCTATAACACCCAGGGTGGTTTGCTTTCTCTGTGCCAGTAGTGGGCAT 4140 GTAGAGTTTGTGTATTGCCAAGTCTGTTGTGAGCCCTTCCACAAGTTTTGTTTAGAGGAG 4200 AACGAGCGCCCTCTGGAGGACCAGCTGGAAAATTGGTGTTGTCGTCGTTGCAAATTCTGT 4260 CACGTTTGTGGAAGGCAACATCAGGCTACAAAGCAGCTGCTGGAGTGTAATAAGTGCCGA 4320 AACAGCTATCACCCTGAGTGCCTGGGACCAAACTACCCCACCAAACCCACAAAGAAGAAG 4380 AAAGTCTGGATCTGTACCAAGTGTGTTCGCTGTAAGAGCTGTGGATCCACAACTCCAGGC 4440 AAAGGGTGGGATGCACAGTGGTCTCATGATTTCTCACTGTGTCATGATTGCGCCAAGCTC 4500 TTTGCTAAAGGAAACTTCTGCCCTCTCTGTGACAAATGTTATGATGATGATGACTATGAG 4560 AGTAAGATGATGCAATGTGGAAAGTGTGATCGCTGGGTCCATTCCAAATGTGAGAATCTT 4620 TCAGGTACAGAAGATGAGATGTATGAGATTCTATCTAATCTGCCAGAAAGTGTGGCCTAC 4680 ACTTGTGTGAACTGTACTGAGCGGCACCCTGCAGAGTGGCGACTGGCCCTTGAAAAAGAG 4740 CTGCAGATTTCTCTGAAGCAAGTTCTGACAGCTTTGTTGAATTCTCGGACTACCAGCCAT 4800 TTGCTACGCTACCGGCAGGCTGCCAAGCCTCCAGACTTAAATCCCGAGACAGAGGAGAGT 4860 ATACCTTCCCGCAGCTCCCCCGAAGGACCTGATCCACCAGTTCTTACTGAGGTCAGCAAA 4920 CAGGATGATCAGCAGCCTTTAGATCTAGAAGGAGTCAAGAGGAAGATGGACCAAGGGAAT 4980 TACACATCTGTGTTGGAGTTCAGTGATGATATTGTGAAGATCATTCAAGCAGCCATTAAT 5040 TCAGATGGAGGACAGCCAGAAATTAAAAAAGCCAACAGCATGGTCAAGTCCTTCTTCATT 5100 CGGCAAATGGAACGTGTTTTTCCATGGTTCAGTGTCAAAAAGTCCAGGTTTTGGGAGCCA 5160 AATAAAGTATCAAGCAACAGTGGGATGTTACCAAACGCAGTGCTTCCACCTTCACTTGAC 5220 CATAATTATGCTCAGTGGCAGGAGCGAGAGGAAAACAGCCACACTGAGCAGCCTCCTTTA 5280 ATGAAGAAAATCATTCCAGCTCCCAAACCCAAAGGTCCTGGAGAACCAGACTCACCAACT 5340 CCTCTGCATCCTCCTACACCACCAATTTTGAGTACTGATAGGAGTCGAGAAGACAGTCCA 5400 GAGCTGAACCCACCCCCAGGCATAGAAGACAATAGACAGTGTGCGTTATGTTTGACTTAT 5460 GGTGATGACAGTGCTAATGATGCTGGTCGTTTACTATATATTGGCCAAAATGAGTGGACA 5520 CATGTAAATTGTGCTTTGTGGTCAGCGGAAGTGTTTGAAGATGATGACGGATCACTAAAG 5580 AATGTGCATATGGCTGTGATCAGGGGCAAGCAGCTGAGATGTGAATTCTGCCAAAAGCCA 5640 GGAGCCACCGTGGGTTGCTGTCTCACATCCTGCACCAGCAACTATCACTTCATGTGTTCC 5700 CGAGCCAAGAACTGTGTCTTTCTGGATGATAAAAAAGTATATTGCCAACGACATCGGGAT 5760 TTGATCAAAGGCGAAGTGGTTCCTGAGAATGGATTTGAAGTTTTCAGAAGAGTGTTTGTG 5820 GACTTTGAAGGAATCAGCTTGAGAAGGAAGTTTCTCAATGGCTTGGAACCAGAAAATATC 5880 CACATGATGATTGGGTCTATGACAATCGACTGCTTAGGAATTCTAAATGATCTCTCCGAC 5940 TGTGAAGATAAGCTCTTTCCTATTGGATATCAGTGTTCCAGGGTATACTGGAGCACCACA 6000 GATGCTCGCAAGCGCTGTGTATATACATGCAAGATAGTGGAGTGCCGTCCTCCAGTCGTA 6060 GAGCCGGATATCAACAGCACTGTTGAACATGATGAAAACAGGACCATTGCCCATAGTCCA 6120 ACATCTTTTACAGAAAGTTCATCAAAAGAGAGTCAAAACACAGCTGAAATTATAAGTCCT 6180 CCATCACCAGACCGACCTCCTCATTCACAAACCTCTGGCTCCTGTTATTATCATGTCATC 6240 TCAAAGGTCCCCAGGATTCGAACACCCAGTTATTCTCCAACACAGAGATCCCCTGGCTGT 6300 CGACCGTTGCCTTCTGCAGGAAGTCCTACCCCAACCACTCATGAAATAGTCACAGTAGGT 6360 GATCCTTTACTCTCCTCTGGACTTCGAAGCATTGGCTCCAGGCGTCACAGTACCTCTTCC 6420 TTATCACCCCAGCGGTCCAAACTCCGGATAATGTCTCCAATGAGAACTGGGAATACTTAC 6480 TCTAGGAATAATGTTTCCTCAGTCTCCACCACCGGGACCGCTACTGATCTTGAATCAAGT 6540 GCCAAAGTAGTTGATCATGTCTTAGGGCCACTGAATTCAAGTACTAGTTTAGGGCAAAAC 6600 ACTTCCACCTCTTCAAATTTGCAAAGGACAGTGGTTACTGTAGGCAATAAAAACAGTCAC 6660 TTGGATGGATCTTCATCTTCAGAAATGAAGCAGTCCAGTGCTTCAGACTTGGTGTCCAAG 6720 AGCTCCTCTTTAAAGGGAGAGAAGACCAAAGTGCTGAGTTCCAAGAGCTCAGAGGGATCT 6780 GCACATAATGTGGCTTACCCTGGAATTCCTAAACTGGCCCCACAGGTTCATAACACAACA 6840 TCTAGAGAACTGAATGTTAGTAAAATCGGCTCCTTTGCTGAACCCTCTTCAGTGTCGTTT 6900 TCTTCTAAAGAGGCCCTCTCCTTCCCACACCTCCATTTGAGAGGGCAAAGGAATGATCGA 6960 GACCAACACACAGATTCTACCCAATCAGCAAACTCCTCTCCAGATGAAGATACTGAAGTC 7020 AAAACCTTGAAGCTATCTGGAATGAGCAACAGATCATCCATTATCAACGAACATATGGGA 7080 TCTAGTTCCAGAGATAGGAGACAGAAAGGGAAAAAATCCTGTAAAGAAACTTTCAAAGAA 7140 AAGCATTCCAGTAAATCTTTTTTGGAACCTGGTCAGGTGACAACTGGTGAGGAAGGAAAC 7200 TTGAAGCCAGAGTTTATGGATGAGGTTTTGACTCCTGAGTATATGGGCCAACGACCATGT 7260 AACAATGTTTCTTCTGATAAGATTGGTGATAAAGGCCTTTCTATGCCAGGAGTCCCCAAA 7320 GCTCCACCCATGCAAGTAGAAGGATCTGCCAAGGAATTACAGGCACCACGGAAACGCACA 7380 GTCAAAGTGACACTGACACCTCTAAAAATGGAAAATGAGAGTCAATCCAAAAATGCCCTG 7440 AAAGAAAGTAGTCCTGCTTCCCCTTTGCAAATAGAGTCAACATCTCCCACAGAACCAATT 7500 TCAGCCTCTGAAAATCCAGGAGATGGTCCAGTGGCCCAACCAAGCCCCAATAATACCTCA 7560 TGCCAGGATTCTCAAAGTAACAACTATCAGAATCTTCCAGTACAGGACAGAAACCTAATG 7620 CTTCCAGATGGCCCCAAACCTCAGGAGGATGGCTCTTTTAAAAGGAGGTATCCCCGTCGC 7680 AGTGCCCGTGCACGTTCTAACATGTTTTTTGGGCTTACCCCACTCTATGGAGTAAGATCC 7740 TATGGTGAAGAAGACATTCCATTCTACAGCAGCTCAACTGGGAAGAAGCGAGGCAAGAGA 7800 TCAGCTGAAGGACAGGTGGATGGGGCCGATGACTTAAGCACTTCAGATGAAGACGACTTA 7860 TACTATTACAACTTCACTAGAACAGTGATTTCTTCAGGTGGAGAGGAACGACTGGCATCC 7920 CATAATTTATTTCGGGAGGAGGAACAGTGTGATCTTCCAAAAATCTCACAGTTGGATGGT 7980 GTTGATGATGGGACAGAGAGTGATACTAGTGTCACAGCCACAACAAGGAAAAGCAGCCAG 8040 ATTCCAAAAAGAAATGGTAAAGAAAATGGAACAGAGAACTTAAAGATTGATAGACCTGAA 8100 GATGCTGGGGAGAAAGAACATGTCACTAAGAGTTCTGTTGGCCACAAAAATGAGCCAAAG 8160 ATGGATAACTGCCATTCTGTAAGCAGAGTTAAAACACAGGGACAAGATTCCTTGGAAGCT 8220 CAGCTCAGCTCATTGGAGTCAAGCCGCAGAGTCCACACAAGTACCCCCTCCGACAAAAAT 8280 TTACTGGACACCTATAATACTGAGCTCCTGAAATCAGATTCAGACAATAACAACAGTGAT 8340 GACTGTGGGAATATCCTGCCTTCAGACATTATGGACTTTGTACTAAAGAATACTCCATCC 8400 ATGCAGGCTTTGGGTGAGAGCCCAGAGTCATCTTCATCAGAACTCCTGAATCTTGGTGAA 8460 GGATTGGGTCTTGACAGTAATCGTGAAAAAGACATGGGTCTTTTTGAAGTATTTTCTCAG 8520 CAGCTGCCTACAACAGAACCTGTGGATAGTAGTGTCTCTTCCTCTATCTCAGCAGAGGAA 8580 CAGTTTGAGTTGCCTCTAGAGCTACCATCTGATCTGTCTGTCTTGACCACCCGGAGTCCC 8640 ACTGTCCCCAGCCAGAATCCCAGTAGACTAGCTGTTATCTCAGACTCAGGGGAGAAGAGA 8700 GTAACCATCACAGAAAAATCTGTAGCCTCCTCTGAAAGTGACCCAGCACTGCTGAGCCCA 8760 GGAGTAGATCCAACTCCTGAAGGCCACATGACTCCTGATCATTTTATCCAAGGACACATG 8820 GATGCAGACCACATCTCTAGCCCTCCTTGTGGTTCAGTAGAGCAAGGTCATGGCAACAAT 8880 CAGGATTTAACTAGGAACAGTAGCACCCCTGGCCTTCAGGTACCTGTTTCCCCAACTGTT 8940 CCCATCCAGAACCAGAAGTATGTGCCCAATTCTACTGATAGTCCTGGCCCGTCTCAGATT 9000 TCCAATGCAGCTGTCCAGACCACTCCACCCCACCTGAAGCCAGCCACTGAGAAACTCATA 9060 GTTGTTAACCAGAACATGCAGCCACTTTATGTTCTCCAAACTCTTCCAAATGGAGTGACC 9120 CAAAAAATCCAATTGACCTCTTCTGTTAGTTCTACACCCAGTGTGATGGAGACAAATACT 9180 TCAGTATTGGGACCCATGGGAGGTGGTCTCACCCTTACCACAGGACTAAATCCAAGCTTG 9240 CCAACTTCTCAATCTTTGTTCCCTTCTGCTAGCAAAGGATTGCTACCCATGTCTCATCAC 9300 CAGCACTTACATTCCTTCCCTGCAGCTACTCAAAGTAGTTTCCCACCAAACATCAGCAAT 9360 CCTCCTTCAGGCCTGCTTATTGGGGTTCAGCCTCCTCCGGATCCCCAACTTTTGGTTTCA 9420 GAATCCAGCCAGAGGACAGACCTCAGTACCACAGTAGCCACTCCATCCTCTGGACTCAAG 9480 AAAAGACCCATATCTCGTCTACAGACCCGAAAGAATAAAAAACTTGCTCCCTCTAGTACC 9540 CCTTCAAACATTGCCCCTTCTGATGTGGTTTCTAATATGACATTGATTAACTTCACACCC 9600 TCCCAGCTTCCTAATCATCCAAGTCTGTTAGATTTGGGGTCACTTAATACTTCATCTCAC 9660 CGAACTGTCCCCAACATCATAAAAAGATCTAAATCTAGCATCATGTATTTTGAACCGGCA 9720 CCCCTGTTACCACAGAGTGTGGGAGGAACTGCTGCCACAGCGGCAGGCACATCAACAATA 9780 AGCCAGGATACTAGCCACCTCACATCAGGGTCTGTGTCTGGCTTGGCATCCAGTTCCTCT 9840 GTCTTGAATGTTGTATCCATGCAAACTACCACAACCCCTACAAGTAGTGCGTCAGTTCCA 9900 GGACACGTCACCTTAACCAACCCAAGGTTGCTTGGTACCCCAGATATTGGCTCAATAAGC 9960 AATCTTTTAATCAAAGCTAGCCAGCAGAGCCTGGGGATTCAGGACCAGCCTGTGGCTTTA 10020 CCGCCAAGTTCAGGAATGTTTCCACAACTGGGGACATCACAGACCCCCTCTACTGCTGCA 10080 ATAACAGCGGCATCTAGCATCTGTGTGCTCCCCTCCACTCAGACTACGGGCATAACAGCC 10140 GCTTCACCTTCTGGGGAAGCAGACGAACACTATCAGCTTCAGCATGTGAACCAGCTCCTT 10200 GCCAGCAAAACTGGGATTCATTCTTCCCAGCGTGATCTTGATTCTGCTTCAGGGCCCCAG 10260 GTATCCAACTTTACCCAGACGGTAGACGCTCCTAATAGCATGGGACTGGAGCAGAACAAG 10320 GCTTTATCCTCAGCTGTGCAAGCCAGCCCCACCTCTCCTGGGGGTTCTCCATCCTCTCCA 10380 TCTTCTGGACAGCGGTCAGCAAGCCCTTCAGTGCCGGGTCCCACTAAACCCAAACCAAAA 10440 ACCAAACGGTTTCAGCTGCCTCTAGACAAAGGGAATGGCAAGAAGCACAATGTTTCCCAT 10500 TTGCGGACCAGTTCTTCTGAAGCACACATTCCAGACCAAGAAACGACATCCCTGACCTCA 10560 GGCACAGGGACTCCAGGAGCAGAGGCTGAGCAGCAGGATACAGCTAGCGTGGAGCAGTCC 10620 TCCCAGAAGGAGTGTGGGCAACCTGCAGGGCAAGTCGCTGTTCTTCCGGAAGTTCAGGTG 10680 ACCCAAAATCCAGCAAATGAACAAGAAAGTGCAGAACCTAAAACAGTGGAAGAAGAGGAA 10740 AGTAATTTCAGCTCCCCACTGATGCTTTGGCTTCAGCAAGAACAAAAGCGGAAGGAAAGC 10800 ATTACTGAGAAAAAACCCAAGAAAGGACTTGTTTTTGAAATTTCCAGTGATGATGGCTTT 10860 CAGATCTGTGCAGAAAGTATTGAAGATGCCTGGAAGTCATTGACAGATAAAGTCCAGGAA 10920 GCTCGATCAAATGCCCGCCTAAAGCAGCTCTCATTTGCAGGTGTTAACGGTTTGAGGATG 10980 CTGGGGATTCTCCATGATGCAGTTGTGTTCCTCATTGAGCAGCTGTCTGGTGCCAAGCAC 11040 TGTCGAAATTACAAATTCCGTTTCCACAAGCCAGAGGAGGCCAATGAACCCCCCTTGAAC 11100 CCTCACGGCTCAGCCAGGGCTGAAGTCCACCTCAGGAAGTCAGCATTTGACATGTTTAAC 11160 TTCCTGGCTTCTAAACATCGTCAGCCTCCTGAATACAACCCCAATGATGAAGAAGAGGAG 11220 GAGGTACAGCTGAAGTCAGCTCGGAGGGCAACTAGCATGGATCTGCCAATGCCCATGCGC 11280 TTCCGGCACTTAAAAAAGACTTCTAAGGAGGCAGTTGGTGTCTACAGGTCTCCCATCCAT 11340 GGCCGGGGTCTTTTCTGTAAGAGAAACATTGATGCAGGTGAGATGGTGATTGAGTATGCC 11400 GGCAACGTCATCCGCTCCATCCAGACTGACAAGCGGGAAAAGTATTACGACAGCAAGGGC 11460 ATTGGTTGCTATATGTTCCGAATTGATGACTCAGAGGTAGTGGATGCCACCATGCATGGA 11520 AATGCTGCACGCTTCATCAATCACTCGTGTGAGCCTAACTGCTATTCTCGGGTCATCAAT 11580 ATTGATGGGCAGAAGCACATTGTCATCTTTGCCATGCGTAAGATCTACCGAGGAGAGGAA 11640 CTCACTTACGACTATAAGTTCCCCATTGAGGATGCCAGCAACAAGCTGCCCTGCAACTGT 11700 GGCGCCAAGAAATGCCGGAAGTTCCTAAACTAAAGCTGCTCTTCTCCCCCAGTGTTGGAG 11760 TGCAAGGAGGCGGGGCCATCCAAAGCAACGCTGAAGGCCTTTTCCAGCAGCTGGGAGCTC 11820 CCGGATTGCGTGGCACAGCTGAGGGGCCTCTGTGATGGCTGAGCTCTCTTATGTCCTATA 11880 CTCACATCAGACATGTGATCATAGTCCCAGAGACAGAGTTGAGGTCTCGAAGAAAAGATC 11940 CATGATCGGCTTTCTCCTGGGGCCCCTCCAATTGTTTACTGTTAGAAAGTGGGAATGGGG 12000 TCCCTAGCAGACTTGCCTGGAAGGAGCCTATTATAGAGGGTTGGTTATGTTGGGAGATTG 12060 GGCCTGAATTTCTCCACAGAAATAAGTTGCCATCCTCAGGTTGGCCCTTTCCCAAGCACT 12120 GTAAGTGAGTGGGTCAGCCAAAGCCCCAAATGGAGGGTTGGTTAGATTCCTGACAGTTTG 12180 CCAGCCAGCCGCCACCTACAGCGTCTGTCGAACAAACAGAGGTCTGGTGGTTTTCCCTAC 12240 TGTCCTCCCACTCGAGAGTTCACTTCTGGTTGGGAGACAGGATTCCTAGCACCTCCGGTG 12300 TCAAAAGGCTGTCATGGGGTTGTGCCAATTAATTACCAAACATTGAGCCTGCAGGCTTTG 12360 AGTGGGAGTGTTGCCCCCAGGAGCCTTATCTCAGCCAATTACCTTTCTTGACAGTAGGAG 12420 CGGCTTCCCTCTCCCATTCCCTCTTCACTCCCTTTTCTTCCTTTCCCCTGTCTTCATGCC 12480 ACTGCTTTCCCATGCTTCTTTCGGTTGTAGGGGAGACTGACTGCCTGCTCAAGGACACTC 12540 CCTGCTGGGCATAGGATGTGCCTGCAAAAAGTTCCCTGAGCCTGTAAGCACTCCAGGTGG 12600 GGAAGTGGACAGGAGCCATTGGTCATAACCAGACAGAATTTGGAAACATTTTCATAAAGC 12660 TCCATGGAGAGTTTTAAAGAAACATATGTAGCATGATTTTGTAGGAGAGGAAAAAGATTA 12720 TTTAAATAGGATTTAAATCATGCAACAACGAGAGTATCACAGCCAGGATGACCCTTGGGT 12780 CCCATTCCTAAGACATGGTTACTTTATTTTCCCCTTGTTAAGACATAGGAAGACTTAATT 12840 TTTAAACGGTCAGTGTCCAGTTGAAGGCAGAACACTAATCAGATTTCAAGGCCCACAACT 12900 TGGGGACTAGACCACCTTATGTTGAGGGAACTCTGCCACCTGCGTGCAACCCACAGCTAA 12960 AGTAAATTCAATGACACTACTGCCCTGATTACTCCTTAGGATGTGGTCAAAACAGCATCA 13020 AATGTTTCTTCTCTTCCTTTCCCCAAGACAGAGTCCTGAACCTGTTAAATTAAGTCATTG 13080 GATTTTACTCTGTTCTGTTTACAGTTTACTATTTAAGGTTTTATAAATGTAAATATATTT 13140 TGTATATTTTTCTATGAGAAGCACTTCATAGGGAGAAGCACTTATGACAAGGCTATTTTT 13200 TAAACCGCGGTATTATCCTAATTTAAAAGAAGATCGGTTTTTAATAATTTTTTATTTTCA 13260 TAGGATGAAGTTAGAGAAAATATTCAGCTGTACACACAAAGTCTGGTTTTTCCTGCCCAA 13320 CTTCCCCCTGGAAGGTGTACTTTTTGTTGTTTAATGTGTAGCTTGTTTGTGCCCTGTTGA 13380 CATAAATGTTTCCTGGGTTTGCTCTTTGACAATAAATGGAGAAGGAAGGTCACCCAACTC 13440 CATTGGGCCACTCCCCTCCTTCCCCTATTGAAGCTCCTCAAAAGGCTACAGTAATATCTT 13500 GATACAACAGATTCTCTTCTTTCCCGCCTCTCTCCTTTCCGGCGCAACTTCCAGAGTGGT 13560 GGGAGACGGCAATCTTTACATTTCCCTCATCTTTCTTACTTCAGAGTTAGCAAACAACAA 13620 GTTGAATGGCAACTTGACATTTTTGCATCACCATCTGCCTCATAGGCCACTCTTTCCTTT 13680 CCCTCTGCCCACCAAGTCCTCATATCTGCAGAGAACCCATTGATCACCTTGTGCCCTCTT 13740 TTGGGGCAGCCTGTTGAAACTGAAGCACAGTCTGACCACTCACGATAAAGCAGATTTTCT 13800 CTGCCTCTGCCACAAGGTTTCAGAGTAGTGTAGTCCAAGTAGAGGGTGGGGCACCCTTTT 13860 CTCGCCGCAAGAAGCCCATTCCTATGGAAGTCTAGCAAAGCAATACGACTCAGCCCAGCA 13920 CTCTCTGCCCCAGGACTCATGGCTCTGCTGTGCCTTCCATCCTGGGCTCCCTTCTCTCCT 13980 GTGACCTTAAGAACTTTGTCTGGTGGCTTTGCTGGAACATTGTCACTGTTTTCACTGTCA 14040 TGCAGGGAGCCCAGCACTGTGGCCAGGATGGCAGAGACTTCCTTGTCATCATGGAGAAGT 14100 GCCAGCAGGGGACTGGGAAAAGCACTCTACCCAGACCTCACCTCCCTTCCTCCTTTTGCC 14160 CATGAACAAGATGCAGTGGCCCTAGGGGTTCCACTAGTGTCTGCTTTCCTTTATTATTGC 14220 ACTGTGTGAGGTTTTTTTGTAAATCCTTGTATTCC14255

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